bims-imicid 2022-06-26 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022‒06‒26
thirty papers selected by
Dylan Ryan
University of Cambridge

Tumor necrosis factor induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport.
NAD kinase promotes Staphylococcus aureus pathogenesis by supporting production of virulence factors and protective enzymes.
The transcription factor RFX5 coordinates antigen-presenting function and resistance to nutrient stress in synovial macrophages.
Kir2.1-mediated membrane potential promotes nutrient acquisition and inflammation through regulation of nutrient transporters.
TCR activation directly stimulates PYGB-dependent glycogenolysis to fuel the early recall response in CD8+ memory T cells.
Mitochondrial cyclophilin D promotes disease tolerance by licensing NK cell development and IL-22 production against influenza virus.
Regulation of Treg Cell Metabolism and Function in Non-Lymphoid Tissues.
Elevated CD4+ T cell glucose metabolism in HIV+ women with diabetes mellitus.
Immunometabolic Reprogramming in Response to HIV Infection Is Not Fully Normalized by Suppressive Antiretroviral Therapy.
Taming metabolic competition via glycolysis inhibition for safe and potent tumor immunotherapy.
The emerging role of microbiota-derived short-chain fatty acids in immunometabolism.
Mitochondrial calcium uniporter promotes phagocytosis-dependent activation of the NLRP3 inflammasome.
Iguratimod Restrains Circulating Follicular Helper T Cell Function by Inhibiting Glucose Metabolism via Hif1α-HK2 Axis in Rheumatoid Arthritis.
Fasciola hepatica Fatty Acid Binding Protein 1 Modulates T cell Polarization by Promoting Dendritic Cell Thrombospondin-1 Secretion Without Affecting Metabolic Homeostasis in Obese Mice.
The effect of HIF on metabolism and immunity.
Interactions between Tryptophan Metabolism, the Gut Microbiome and the Immune System as Potential Drivers of Non-Alcoholic Fatty Liver Disease (NAFLD) and Metabolic Diseases.
Dichloroacetate improves systemic energy balance and feeding behavior during sepsis.
The metabolic impact of bacterial infection in the gut.
Soluble TREM2 levels reflect the recruitment and expansion of TREM2+ macrophages that localize to fibrotic areas and limit NASH.
Hypercholesterolemia Negatively Regulates P2X7-Induced Cellular Function in CD4+ and CD8+ T-Cell Subsets from B6 Mice Fed a High-Fat Diet.
Very-low-density lipoprotein receptor-enhanced lipid metabolism in pancreatic stellate cells promotes pancreatic fibrosis.
The Spike Protein of SARS-CoV-2 Impairs Lipid Metabolism and Increases Susceptibility to Lipotoxicity: Implication for a Role of Nrf2.
Myristic Acid Supplementation Aggravates High Fat Diet-Induced Adipose Inflammation and Systemic Insulin Resistance in Mice.
Metabolomics Analysis of PK-15 Cells with Pseudorabies Virus Infection Based on UHPLC-QE-MS.
Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease - novel insights into cellular communication circuits.
The Novel Role of Metabolism-Associated Molecular Patterns in Sepsis.
STING signaling sensing of DRP1-dependent mtDNA release in kupffer cells contributes to lipopolysaccharide-induced liver injury in mice.
A small molecule redistributes iron in ferroportin-deficient mice and patient-derived primary macrophages.
Development of a novel LDHA inhibitor with potent antitumor activity and immune activation.
PTEN is required for human Treg suppression of costimulation in vitro.

Science. 2022 Jun 24. 376(6600): eabh2841

Tumor necrosis factor induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport.

Francisco J Roca, Laura J Whitworth, Hiran A Prag, Michael P Murphy, Lalita Ramakrishnan.

Tumor necrosis factor (TNF) is a critical host resistance factor against tuberculosis. However, excess TNF produces susceptibility by increasing mitochondrial reactive oxygen species (mROS), which initiate a signaling cascade to cause pathogenic necrosis of mycobacterium-infected macrophages. In zebrafish, we identified the mechanism of TNF-induced mROS in tuberculosis. Excess TNF in mycobacterium-infected macrophages elevates mROS production by reverse electron transport (RET) through complex I. TNF-activated cellular glutamine uptake leads to an increased concentration of succinate, a Krebs cycle intermediate. Oxidation of this elevated succinate by complex II drives RET, thereby generating the mROS superoxide at complex I. The complex I inhibitor metformin, a widely used antidiabetic drug, prevents TNF-induced mROS and necrosis of Mycobacterium tuberculosis-infected zebrafish and human macrophages; metformin may therefore be useful in tuberculosis therapy.

DOI: https://doi.org/10.1126/science.abh2841
Elife. 2022 06 20. pii: e79941. [Epub ahead of print]11

NAD kinase promotes Staphylococcus aureus pathogenesis by supporting production of virulence factors and protective enzymes.

Clarisse Leseigneur, Laurent Boucontet, Magalie Duchateau, Javier Pizarro-Cerda, Mariette Matondo, Emma Colucci-Guyon, Olivier Dussurget.

  Nicotinamide adenine dinucleotide phosphate (NADPH) is the primary electron donor for reductive reactions that are essential for the biosynthesis of major cell components in all organisms. Nicotinamide adenine dinucleotide kinase (NADK) is the only enzyme that catalyzes the synthesis of NADP(H) from NAD(H). While the enzymatic properties and physiological functions of NADK have been thoroughly studied, the role of NADK in bacterial pathogenesis remains unknown. Here, we used CRISPR interference to knock down NADK gene expression to address the role of this enzyme in Staphylococcus aureus pathogenic potential. We find that NADK inhibition drastically decreases mortality of zebrafish infected with S. aureus. Furthermore, we show that NADK promotes S. aureus survival in infected macrophages by protecting bacteria from antimicrobial defense mechanisms. Proteome-wide data analysis revealed that production of major virulence-associated factors is sustained by NADK. We demonstrate that NADK is required for expression of the quorum-sensing response regulator AgrA, which controls critical S. aureus virulence determinants. These findings support a key role for NADK in bacteria survival within innate immune cells and the host during infection.

Keywords:  AgrA; NADK; infection; infectious disease; macrophage; microbiology; staphylococcus; virulence; zebrafish

DOI:  https://doi.org/10.7554/eLife.79941
Nat Metab. 2022 Jun 23.

The transcription factor RFX5 coordinates antigen-presenting function and resistance to nutrient stress in synovial macrophages.

Zhaolan Hu, Tuantuan V Zhao, Tao Huang, Shozo Ohtsuki, Ke Jin, Isabel N Goronzy, Bowen Wu, Matthew P Abdel, Jacob W Bettencourt, Gerald J Berry, Jörg J Goronzy, Cornelia M Weyand.

Tissue macrophages (Mϕ) are essential effector cells in rheumatoid arthritis (RA), contributing to autoimmune tissue inflammation through diverse effector functions. Their arthritogenic potential depends on their proficiency to survive in the glucose-depleted environment of the inflamed joint. Here, we identify a mechanism that links metabolic adaptation to nutrient stress with the efficacy of tissue Mϕ to activate adaptive immunity by presenting antigen to tissue-invading T cells. Specifically, Mϕ populating the rheumatoid joint produce and respond to the small cytokine CCL18, which protects against cell death induced by glucose withdrawal. Mechanistically, CCL18 induces the transcription factor RFX5 that selectively upregulates glutamate dehydrogenase 1 (GLUD1), thus enabling glutamate utilization to support energy production. In parallel, RFX5 enhances surface expression of HLA-DR molecules, promoting Mϕ-dependent expansion of antigen-specific T cells. These data place CCL18 at the top of a RFX5-GLUD1 survival pathway and couple adaptability to nutrient conditions in the tissue environment to antigen-presenting function in autoimmune tissue inflammation.

DOI: https://doi.org/10.1038/s42255-022-00585-x
Nat Commun. 2022 Jun 21. 13(1): 3544

Kir2.1-mediated membrane potential promotes nutrient acquisition and inflammation through regulation of nutrient transporters.

Weiwei Yu, Zhen Wang, Xiafei Yu, Yonghui Zhao, Zili Xie, Kailian Zhang, Zhexu Chi, Sheng Chen, Ting Xu, Danlu Jiang, Xingchen Guo, Mobai Li, Jian Zhang, Hui Fang, Dehang Yang, Yuxian Guo, Xuyan Yang, Xue Zhang, Yingliang Wu, Wei Yang, Di Wang.

Immunometabolism contributes to inflammation, but how activated macrophages acquire extracellular nutrients to fuel inflammation is largely unknown. Here, we show that the plasma membrane potential (Vm) of macrophages mediated by Kir2.1, an inwardly-rectifying K+ channel, is an important determinant of nutrient acquisition and subsequent metabolic reprogramming promoting inflammation. In the absence of Kir2.1 activity, depolarized macrophage Vm lead to a caloric restriction state by limiting nutrient uptake and concomitant adaptations in nutrient conservation inducing autophagy, AMPK (Adenosine 5'-monophosphate-activated protein kinase), and GCN2 (General control nonderepressible 2), which subsequently depletes epigenetic substrates feeding histone methylation at loci of a cluster of metabolism-responsive inflammatory genes, thereby suppressing their transcription. Kir2.1-mediated Vm supports nutrient uptake by facilitating cell-surface retention of nutrient transporters such as 4F2hc and GLUT1 by its modulation of plasma membrane phospholipid dynamics. Pharmacological targeting of Kir2.1 alleviated inflammation triggered by LPS or bacterial infection in a sepsis model and sterile inflammation in human samples. These findings identify an ionic control of macrophage activation and advance our understanding of the immunomodulatory properties of Vm that links nutrient inputs to inflammatory diseases.

DOI: https://doi.org/10.1038/s41467-022-31149-y
Mol Cell. 2022 Jun 17. pii: S1097-2765(22)00538-X. [Epub ahead of print]

TCR activation directly stimulates PYGB-dependent glycogenolysis to fuel the early recall response in CD8+ memory T cells.

Huafeng Zhang, Jincheng Liu, Zhuoshun Yang, Liping Zeng, Keke Wei, Liyan Zhu, Liang Tang, Dianheng Wang, Yabo Zhou, Jiadi Lv, Nannan Zhou, Ke Tang, Jingwei Ma, Bo Huang.

  Glycolysis facilitates the rapid recall response of CD8+ memory T (Tm) cells. However, it remains unclear whether Tm cells uptake exogenous glucose or mobilize endogenous sugar to fuel glycolysis. Here, we show that intracellular glycogen rather than extracellular glucose acts as the major carbon source for the early recall response. Following antigenic stimulation, Tm cells exhibit high glycogen phosphorylase (brain form, PYGB) activity, leading to glycogenolysis and release of glucose-6-phosphate (G6P). Elevated G6P mainly flows to glycolysis but is also partially channeled to the pentose phosphate pathway, which maintains the antioxidant capacity necessary for later recall stages. Mechanistically, TCR signaling directly induces phosphorylation of PYGB by LCK-ZAP70. Functionally, the glycogenolysis-fueled early recall response of CD8+ Tm cells accelerates the clearance of OVA-Listeria monocytogenes in an infected mouse model. Thus, we uncover a specific dependency on glycogen for the initial activation of memory T cells, which may have therapeutic implications for adaptive immunity.

Keywords:  CD8(+) memory T cells; PYGB; ZAP70; glycogen; recall response

DOI:  https://doi.org/10.1016/j.molcel.2022.06.002
Cell Rep. 2022 Jun 21. pii: S2211-1247(22)00760-4. [Epub ahead of print]39(12): 110974

Mitochondrial cyclophilin D promotes disease tolerance by licensing NK cell development and IL-22 production against influenza virus.

Jeffrey Downey, Haley E Randolph, Erwan Pernet, Kim A Tran, Shabaana A Khader, Irah L King, Luis B Barreiro, Maziar Divangahi.

  Severity of pulmonary viral infections, including influenza A virus (IAV), is linked to excessive immunopathology, which impairs lung function. Thus, the same immune responses that limit viral replication can concomitantly cause lung damage that must be countered by largely uncharacterized disease tolerance mechanisms. Here, we show that mitochondrial cyclophilin D (CypD) protects against IAV via disease tolerance. CypD-/- mice are significantly more susceptible to IAV infection despite comparable antiviral immunity. This susceptibility results from damage to the lung epithelial barrier caused by a reduction in interleukin-22 (IL-22)-producing natural killer (NK) cells. Transcriptomic and functional data reveal that CypD-/- NK cells are immature and have altered cellular metabolism and impaired IL-22 production, correlating with dysregulated bone marrow lymphopoiesis. Administration of recombinant IL-22 or transfer of wild-type (WT) NK cells abrogates pulmonary damage and protects CypD-/- mice after IAV infection. Collectively, these results demonstrate a key role for CypD in NK cell-mediated disease tolerance.

Keywords:  CP: Immunology; CP: Microbiology; IL-22; NK cells; cyclophilin D; disease tolerance; influenza; lymphopoiesis

DOI:  https://doi.org/10.1016/j.celrep.2022.110974
Front Immunol. 2022 ;13 909705

Regulation of Treg Cell Metabolism and Function in Non-Lymphoid Tissues.

Kai Yang.

  Regulator T cells (Tregs) play pivotal roles in maintaining immune tolerance and regulating immune responses against pathogens and tumors. Reprogramming of cellular metabolism has been determined as a crucial process that connects microenvironmental cues and signaling networks to influence homeostasis and function of tissue Tregs. In adaptation to a variety of non-lymphoid tissues, Tregs coordinate local immune signals and signaling networks to rewire cellular metabolic programs to sustain their suppressive function. Altered Treg metabolism in turn shapes Treg activation and function. In light of the advanced understanding of immunometabolism, manipulation of systemic metabolites has been emerging as an attractive strategy aiming to modulate metabolism and function of tissue Tregs and improve the treatment of immune-related diseases. In this review, we summarize key immune signals and metabolic programs involved in the regulation of tissue Tregs, review the mechanisms underlying the differentiation and function of Tregs in various non-lymphoid tissues, and discuss therapeutic intervention of metabolic modulators of tissue Tregs for the treatment of autoimmune diseases and cancer.

Keywords:  Treg function; Treg homeostasis; Treg metabolism; metabolic signaling; tissue Treg cells

DOI:  https://doi.org/10.3389/fimmu.2022.909705
AIDS. 2022 Jun 21.

Elevated CD4+ T cell glucose metabolism in HIV+ women with diabetes mellitus.

Tiffany R Butterfield, David B Hanna, Robert C Kaplan, Xiaonan Xue, Jorge R Kizer, Helen G Durkin, Seble G Kassaye, Marek Nowicki, Phyllis C Tien, Elizabeth T Golub, Michelle A Floris-Moore, Kehmia Titanji, Margaret A Fischl, Sonya Heath, Clovis S Palmer, Alan L Landay, Joshua J Anzinger.

OBJECTIVE: Immune dysfunction and chronic inflammation are characteristic of HIV infection and diabetes mellitus (DM), with CD4+ T cell metabolism implicated in the pathogenesis of each disease. However, there is limited information on CD4+ T cell metabolism in HIV+ persons with DM. We examined CD4+ T cell glucose metabolism in HIV+ women with and without DM.DESIGN: A case-control study was used to compare CD4+ T cell glucose metabolism in women with HIV with or without DM.
METHODS: Non-diabetic (HIV+DM-, N = 20) or type 2 diabetic HIV+ women with (HIV+DM+, N = 16) or without (HIV+DMTx+, N = 18) anti-diabetic treatment were identified from the WIHS and matched for age, race/ethnicity, smoking status and CD4 count. CD4+ T cell immunometabolism was examined by flow cytometry, microfluidic qRT-PCR of metabolic genes, and Seahorse extracellular flux analysis of stimulated CD4+ T cells.
RESULTS: HIV+DM+ displayed a significantly elevated proportion of CD4+ T cells expressing the immunometabolic marker GLUT1 compared to HIV+DMTx+ and HIV+DM- (p = 0.04 and p = 0.01, respectively). Relative expression of genes encoding key enzymes for glucose metabolism pathways were elevated in CD4+ T cells of HIV+DM+ compared to HIV+DMTx+ and HIV+DM-. TCR-activated CD4+ T cells from HIV+DM+ showed elevated glycolysis and oxidative phosphorylation compared to HIV+DM-.
CONCLUSIONS: CD4+ T cells from HIV+DM+ have elevated glucose metabolism. Treatment of DM among women with HIV may partially correct CD4+ T cell metabolic dysfunction.

DOI: https://doi.org/10.1097/QAD.0000000000003272
Viruses. 2022 Jun 15. pii: 1313. [Epub ahead of print]14(6):

Immunometabolic Reprogramming in Response to HIV Infection Is Not Fully Normalized by Suppressive Antiretroviral Therapy.

Pragney Deme, Leah H Rubin, Danyang Yu, Yanxun Xu, Gertrude Nakigozi, Noeline Nakasujja, Aggrey Anok, Alice Kisakye, Thomas C Quinn, Steven J Reynolds, Richard Mayanja, James Batte, Maria J Wawer, Ned C Sacktor, Deanna Saylor, Norman J Haughey.

  BACKGROUND: HIV infection results in immunometabolic reprogramming. While we are beginning to understand how this metabolic reprogramming regulates the immune response to HIV infection, we do not currently understand the impact of ART on immunometabolism in people with HIV (PWH).METHODS: Serum obtained from HIV-infected (n = 278) and geographically matched HIV seronegative control subjects (n = 300) from Rakai Uganda were used in this study. Serum was obtained before and ~2 years following the initiation of ART from HIV-infected individuals. We conducted metabolomics profiling of the serum and focused our analysis on metabolic substrates and pathways assocaited with immunometabolism.
RESULTS: HIV infection was associated with metabolic adaptations that implicated hyperactive glycolysis, enhanced formation of lactate, increased activity of the pentose phosphate pathway (PPP), decreased β-oxidation of long-chain fatty acids, increased utilization of medium-chain fatty acids, and enhanced amino acid catabolism. Following ART, serum levels of ketone bodies, carnitine, and amino acid metabolism were normalized, however glycolysis, PPP, lactate production, and β-oxidation of long-chain fatty acids remained abnormal.
CONCLUSION: Our findings suggest that HIV infection is associated with an increased immunometabolic demand that is satisfied through the utilization of alternative energetic substrates, including fatty acids and amino acids. ART alone was insufficient to completely restore this metabolic reprogramming to HIV infection, suggesting that a sustained impairment of immunometabolism may contribute to chronic immune activation and comorbid conditions in virally suppressed PWH.

Keywords:  HIV infection; amino acid catabolism; antiretroviral therapy; comorbid conditions; fatty acid oxidation; glucose oxidation; immunometabolism

DOI:  https://doi.org/10.3390/v14061313
Biochem Pharmacol. 2022 Jun 21. pii: S0006-2952(22)00247-7. [Epub ahead of print] 115153

Taming metabolic competition via glycolysis inhibition for safe and potent tumor immunotherapy.

Jun Lei, Yi Yang, Zhaoliang Lu, Haiyan Pan, Jialing Fang, Baowei Jing, Yongshun Chen, Lei Yin.

  Metabolic competition between tumors and T cells is fierce in the tumor microenvironment (TME). Tumors usually exhaust glucose and accumulate lactic acid in TME. Nutrient deprivation and lactic acid accumulation in TME blunt T cell functions and antitumor immune responses. Here, we reported that glycolysis-related genes were upregulated in melanoma patients with weak immune responses and T cell poorly infiltrated tumors of BRCA and COAD patients. Dimethyl fumarate (DMF), a GAPDH inhibitor, which is FDA proved to treat autoimmune diseases was identified to promote oxidative pentose phosphate pathway through glucose-6-phosphate dehydrogenase (G6PD) but to suppress aerobic glycolysis and oxidative phosphorylation in tumor cells. Additionally, DMF normalized metabolic competition between tumors and T cells, thus potentiate antitumor responses of tumor infiltrating CD8+ T lymphocytes (TILs). Moreover, DMF optimized the efficiency of immune checkpoint therapy and interleukin-2 (IL-2) therapy while eliminating severe toxicity induced by IL-2 therapy. This study indicates a novel clinically feasible therapy strategy aiming shared metabolic pathway of tumors and T cells for effective and less toxic tumor immunotherapy.

Keywords:  Immunotherapy; Metabolic competition; Metabolic regulation; T cell; Tumor microenvironment; Tumors

DOI:  https://doi.org/10.1016/j.bcp.2022.115153
Int Immunopharmacol. 2022 Jun 21. pii: S1567-5769(22)00467-2. [Epub ahead of print]110 108983

The emerging role of microbiota-derived short-chain fatty acids in immunometabolism.

Saade Abdalkareem Jasim, Maria Jade Catalan Opulencia, Andrés Alexis Ramírez-Coronel, Walid Kamal Abdelbasset, Murtadha Hasan Abed, Alexander Markov, Ghaidaa Raheem Lateef Al-Awsi, Jamshid Azamatovich Shamsiev, Ali Thaeer Hammid, Mohammed Nader Shalaby, Sajad Karampoor, Rasoul Mirzaei.

  The accumulating evidence revealed that microbiota plays a significant function in training, function, and the induction of host immunity. Once this interaction (immune system-microbiota) works correctly, it enables the production of protective responses against pathogens and keeps the regulatory pathways essential for maintaining tolerance to innocent antigens. This concept of immunity and metabolic activity redefines the realm of immunometabolism, paving the way for innovative therapeutic interventions to modulate immune cells through immune metabolic alterations. A body of evidence suggests that microbiota-derived metabolites, including short-chain fatty acids (SCFAs) such as butyrate, acetate, and propionate, play a key role in immune balance. SCFAs act on many cell types to regulate various vital biological processes, including host metabolism, intestinal function, and the immune system. Such SCFAs generated by gut bacteria also impact immunity, cellular function, and immune cell fate. This is a new concept of immune metabolism, and better knowledge about how lifestyle affects intestinal immunometabolism is crucial for preventing and treating disease. In this review article, we explicitly focus on the function of SCFAs in the metabolism of immune cells, especially macrophages, neutrophils, dendritic cells (DCs), B cells, T (Th) helper cells, and cytotoxic T cells (CTLs).

Keywords:  Immune modulation; Immunity; Immunometabolism; Microbiota; Short-chain fatty acids

DOI:  https://doi.org/10.1016/j.intimp.2022.108983
Proc Natl Acad Sci U S A. 2022 Jun 28. 119(26): e2123247119

Mitochondrial calcium uniporter promotes phagocytosis-dependent activation of the NLRP3 inflammasome.

Hong Dong, Bao Zhao, Jianwen Chen, Zihao Liu, Xinghui Li, Lupeng Li, Haitao Wen.

  Mitochondria, a highly metabolically active organelle, have been shown to play an essential role in regulating innate immune function. Mitochondrial Ca2+ uptake via the mitochondrial Ca2+ uniporter (MCU) is an essential process regulating mitochondrial metabolism by targeting key enzymes involved in the tricarboxylic acid cycle (TCA). Accumulative evidence suggests MCU-dependent mitochondrial Ca2+ signaling may bridge the metabolic reprogramming and regulation of immune cell function. However, the mechanism by which MCU regulates inflammation and its related disease remains elusive. Here we report a critical role of MCU in promoting phagocytosis-dependent activation of NLRP3 (nucleotide-binding domain, leucine-rich repeat containing family, pyrin domain-containing 3) inflammasome by inhibiting phagolysosomal membrane repair. Myeloid deletion of MCU (McuΔmye) resulted in an attenuated phagolysosomal rupture, leading to decreased caspase-1 cleavage and interleukin (IL)-1β release, in response to silica or alum challenge. In contrast, other inflammasome agonists such as adenosine triphosphate (ATP), nigericin, poly(dA:dT), and flagellin induced normal IL-1β release in McuΔmye macrophages. Mechanistically, we demonstrated that decreased NLRP3 inflammasome activation in McuΔmye macrophages was caused by improved phagolysosomal membrane repair mediated by ESCRT (endosomal sorting complex required for transport)-III complex. Furthermore, McuΔmye mice showed a pronounced decrease in immune cell recruitment and IL-1β production in alum-induced peritonitis, a typical IL-1-dependent inflammation model. In sum, our results identify a function of MCU in promoting phagocytosis-dependent NLRP3 inflammatory response via an ESCRT-mediated phagolysosomal membrane repair mechanism.

Keywords:  ESCRT; MCU; inflammasome; phagosome

DOI:  https://doi.org/10.1073/pnas.2123247119
Front Immunol. 2022 ;13 757616

Iguratimod Restrains Circulating Follicular Helper T Cell Function by Inhibiting Glucose Metabolism via Hif1α-HK2 Axis in Rheumatoid Arthritis.

Ziran Bai, Zhimin Lu, Rui Liu, Yawei Tang, Xiaokang Ye, Minli Jin, Guan Wang, Xia Li.

  Iguratimod (IGU) is a novel disease modified anti-rheumatic drug, which has been found to act directly on B cells for inhibiting the production of antibodies in rheumatoid arthritis (RA) patients. Follicular helper T (Tfh) cells, a key T cell subsets in supporting B cell differentiation and antibody production, have been shown to play critical roles in RA. However, whether IGU can inhibit RA Tfh cells which further restrains B cell function remains unclear. Here, we aimed to explore the roles of IGU in regulating RA circulating Tfh (cTfh) cell function and investigate the potential mechanism associated with cell glucose metabolism. In our study, we found that IGU could act on RA-CD4+ T cells to reduce T cell-dependent antibody production. IGU decreased the percentage of RA cTfh cells and the expression of Tfh cell-related molecules and cytokines which were involved in B cell functions. Importantly, our data showed that IGU significantly restrained the cTfh cell function by inhibiting glucose metabolism, which relied on Hif1α-HK2 axis. In summary, we clarified a new target and mechanism of IGU by restraining RA cTfh cell function via inhibiting Hif1α-HK2-glucose metabolism axis. Our study demonstrates the potential application of IGU in the treatment of diseases related to abnormal metabolism and function of Tfh cells.

Keywords:  Hif1α-HK2 axis; circulating follicular helper T cells; glucose metabolism; iguratimod; rheumatoid arthritis

DOI:  https://doi.org/10.3389/fimmu.2022.757616
Front Immunol. 2022 ;13 884663

Fasciola hepatica Fatty Acid Binding Protein 1 Modulates T cell Polarization by Promoting Dendritic Cell Thrombospondin-1 Secretion Without Affecting Metabolic Homeostasis in Obese Mice.

Anna Zawistowska-Deniziak, Joost M Lambooij, Alicja Kalinowska, Thiago A Patente, Maciej Łapiński, Hendrik J P van der Zande, Katarzyna Basałaj, Clarize M de Korne, Mathilde A M Chayé, Thomas A Gasan, Luke J Norbury, Martin Giera, Arnaud Zaldumbide, Hermelijn H Smits, Bruno Guigas.

  Background: The parasitic trematode Fasciola hepatica evades host immune defenses through secretion of various immunomodulatory molecules. Fatty Acid Binding Proteins (fhFABPs) are among the main excreted/secreted proteins and have been shown to display anti-inflammatory properties. However, little is currently known regarding their impact on dendritic cells (DCs) and their subsequent capacity to prime specific CD4+ T cell subsets.Methodology/Principal Findings: The immunomodulatory effects of both native F. hepatica extracts and recombinant fhFABPs were assessed on monocyte-derived human DCs (moDCs) and the underlying mechanism was next investigated using various approaches, including DC-allogenic T cell co-culture and DC phenotyping through transcriptomic, proteomic and FACS analyses. We mainly showed that fhFABP1 induced a tolerogenic-like phenotype in LPS-stimulated moDCs characterized by a dose-dependent increase in the cell-surface tolerogenic marker CD103 and IL-10 secretion, while DC co-stimulatory markers were not affected. A significant decrease in secretion of the pro-inflammatory cytokines IL-12p70 and IL-6 was also observed. In addition, these effects were associated with an increase in both Th2-on-Th1 ratio and IL-10 secretion by CD4+ T cells following DC-T cell co-culture. RNA sequencing and targeted proteomic analyses identified thrombospondin-1 (TSP-1) as a non-canonical factor highly expressed and secreted by fhFABP1-primed moDCs. The effect of fhFABP1 on T cell skewing was abolished when using a TSP-1 blocking antibody during DC-T cell co-culture. Immunomodulation by helminth molecules has been linked to improved metabolic homeostasis during obesity. Although fhFABP1 injection in high-fat diet-fed obese mice induced a potent Th2 immune response in adipose tissue, it did not improved insulin sensitivity or glucose homeostasis.
Conclusions/Significance: We show that fhFABP1 modulates T cell polarization, notably by promoting DC TSP-1 secretion in vitro, without affecting metabolic homeostasis in a mouse model of type 2 diabetes.

Keywords:  TSP-1; Th1; Th2; dendritic cells; helminths; immunometabolism; liver fluke; metaflammation

DOI:  https://doi.org/10.3389/fimmu.2022.884663
Nat Rev Nephrol. 2022 Jun 20.

The effect of HIF on metabolism and immunity.

Cormac T Taylor, Carsten C Scholz.

Cellular hypoxia occurs when the demand for sufficient molecular oxygen needed to produce the levels of ATP required to perform physiological functions exceeds the vascular supply, thereby leading to a state of oxygen depletion with the associated risk of bioenergetic crisis. To protect against the threat of hypoxia, eukaryotic cells have evolved the capacity to elicit oxygen-sensitive adaptive transcriptional responses driven primarily (although not exclusively) by the hypoxia-inducible factor (HIF) pathway. In addition to the canonical regulation of HIF by oxygen-dependent hydroxylases, multiple other input signals, including gasotransmitters, non-coding RNAs, histone modifiers and post-translational modifications, modulate the nature of the HIF response in discreet cell types and contexts. Activation of HIF induces various effector pathways that mitigate the effects of hypoxia, including metabolic reprogramming and the production of erythropoietin. Drugs that target the HIF pathway to induce erythropoietin production are now approved for the treatment of chronic kidney disease-related anaemia. However, HIF-dependent changes in cell metabolism also have profound implications for functional responses in innate and adaptive immune cells, and thereby heavily influence immunity and the inflammatory response. Preclinical studies indicate a potential use of HIF therapeutics to treat inflammatory diseases, such as inflammatory bowel disease. Understanding the links between HIF, cellular metabolism and immunity is key to unlocking the full therapeutic potential of drugs that target the HIF pathway.

DOI: https://doi.org/10.1038/s41581-022-00587-8
Metabolites. 2022 Jun 02. pii: 514. [Epub ahead of print]12(6):

Interactions between Tryptophan Metabolism, the Gut Microbiome and the Immune System as Potential Drivers of Non-Alcoholic Fatty Liver Disease (NAFLD) and Metabolic Diseases.

Charlotte Teunis, Max Nieuwdorp, Nordin Hanssen.

  The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and therefore is its burden of disease as NALFD is a risk factor for cirrhosis and is associated with other metabolic conditions such as type II diabetes, obesity, dyslipidaemia and atherosclerosis. Linking these cardiometabolic diseases is a state of low-grade inflammation, with higher cytokines and c-reactive protein levels found in individuals with NAFLD, obesity and type II diabetes. A possible therapeutic target to decrease this state of low-grade inflammation is the metabolism of the essential amino-acid tryptophan. Its three main metabolic pathways (kynurenine pathway, indole pathway and serotonin/melatonin pathway) result in metabolites such as kynurenic acid, xanturenic acid, indole-3-propionic acid and serotonin/melatonin. The kynurenine pathway is regulated by indoleamine 2,3-dioxygenase (IDO), an enzyme that is upregulated by pro-inflammatory molecules such as INF, IL-6 and LPS. Higher activity of IDO is associated with increased inflammation and fibrosis in NAFLD, as well with increased glucose levels, obesity and atherosclerosis. On the other hand, increased concentrations of the indole pathway metabolites, regulated by the gut microbiome, seem to result in more favorable outcomes. This narrative review summarizes the interactions between tryptophan metabolism, the gut microbiome and the immune system as potential drivers of cardiometabolic diseases in NAFLD.

Keywords:  MAFLD; NAFLD; gut microbiota; metabolic disease; tryptophan metabolism

DOI:  https://doi.org/10.3390/metabo12060514
JCI Insight. 2022 Jun 22. pii: e153944. [Epub ahead of print]7(12):

Dichloroacetate improves systemic energy balance and feeding behavior during sepsis.

Tae Seok Oh, Manal Zabalawi, Shalini Jain, David Long, Peter W Stacpoole, Charles E McCall, Matthew A Quinn.

  Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to an infection. The metabolic aberrations associated with sepsis underly an acute and organism-wide hyperinflammatory response and multiple organ dysfunction; however, crosstalk between systemic metabolomic alterations and metabolic reprogramming at organ levels remains unknown. We analyzed substrate utilization by the respiratory exchange ratio, energy expenditure, metabolomic screening, and transcriptional profiling in a cecal ligation and puncture model to show that sepsis increases circulating free fatty acids and acylcarnitines but decreases levels of amino acids and carbohydrates, leading to a drastic shift in systemic fuel preference. Comparative analysis of previously published metabolomics from septic liver indicated a positive correlation with hepatic and plasma metabolites during sepsis. In particular, glycine deficiency was a common abnormality of the plasma and liver during sepsis. Interrogation of the hepatic transcriptome in septic mice suggested that the septic liver may contribute to systemic glycine deficiency by downregulating genes involved in glycine synthesis. Interestingly, intraperitoneal injection of the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate reversed sepsis-induced anorexia, energy imbalance, inflammation, dyslipidemia, hypoglycemia, and glycine deficiency. Collectively, our data indicated that PDK inhibition rescued systemic energy imbalance and metabolic dysfunction in sepsis partly through restoration of hepatic fuel metabolism.

Keywords:  Bacterial infections; Immunology

DOI:  https://doi.org/10.1172/jci.insight.153944
FEBS J. 2022 Jun 22.

The metabolic impact of bacterial infection in the gut.

Pooja Chaukimath, Gad Frankel, Sandhya S Visweswariah.

  Bacterial infections of the gut are one of the major causes of morbidity and mortality worldwide. The interplay between the pathogen and the host is finely balanced, with the bacteria evolving to proliferate and establish infection. In contrast, the host mounts a response to first restrict and then eliminate the infection. The intestine is a rapidly proliferating tissue, and metabolism is tuned to cater to the demands of proliferation and differentiation along the crypt-villus axis (CVA) in the gut. As bacterial pathogens encounter the intestinal epithelium, they elicit changes in the host cell, and core metabolic pathways such as the tricarboxylic acid (TCA) cycle, lipid metabolism, and glycolysis are affected. This review highlights the mechanisms utilized by diverse gut bacterial pathogens to subvert host metabolism and describes host responses to the infection.

Keywords:  gut pathogen; infection; intestinal epithelial cell; metabolism

DOI:  https://doi.org/10.1111/febs.16562
J Hepatol. 2022 Jun 15. pii: S0168-8278(22)00359-2. [Epub ahead of print]

Soluble TREM2 levels reflect the recruitment and expansion of TREM2+ macrophages that localize to fibrotic areas and limit NASH.

Tim Hendrikx, Florentina Porsch, Máté G Kiss, Dragana Rajcic, Nikolina Papac-Miličević, Constanze Hoebinger, Laura Göderle, Anastasiya Hladik, Lisa E Shaw, Hauke Horstmann, Sylvia Knapp, Sophia Derdak, Martin Bilban, Lena Heintz, Marcin Krawczyk, Rafael Paternostro, Michael Trauner, Matthias Farlik, Dennis Wolf, Christoph J Binder.

  BACKGROUND & AIMS: Due to the complex multifactorial origin and an incomplete understanding of the underlying disease mechanisms, progression of non-alcoholic fatty liver disease (NAFLD) into advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis is predicted to become the primary indication for liver transplantation. Hence, there is an unmet need to identify novel targets to improve treatment strategies.METHODS: In an unbiased approach using bulk RNA sequencing, the hepatic molecular response to lipid-dependent dietary intervention was assessed in mice. Spatial mapping, bone marrow transplantation in two complementary murine models and single cell sequencing was applied to functionally characterize the role of bone marrow-derived TREM2+ macrophage populations in NASH.
RESULTS: We found that the hepatic transcriptomic profile during steatohepatitis mirrors the dynamics of recruited bone marrow-derived monocytes that already acquire increased expression of Trem2 in circulation. Increased Trem2 expression was reflected by elevated levels of systemic soluble TREM2 in mice and humans with NASH. In addition, soluble TREM2 levels transpire as a superior marker over traditionally used laboratory parameters to distinguish between different fatty liver disease stages of NAFLD in two separate clinical cohorts. Spatial transcriptomics revealed that TREM2+ macrophages localize to sites of hepatocellular damage, inflammation and fibrosis in the steatotic liver. Finally, using multiple murine models and in vitro experiments, we demonstrate that hematopoietic Trem2 deficiency causes defective lipid handling and extracellular matrix remodeling, resulting in exacerbated steatohepatitis, cell death and fibrosis.
CONCLUSIONS: Our study highlights the functional properties of bone marrow-derived TREM2+ macrophages and implies the clinical relevance of systemic soluble TREM2 levels in the context of NASH.
LAY SUMMARY: Our study defines the origin and function of hepatic TREM2+ macrophages and describes a mechanism by which they are critically involved in protecting from NASH. Furthermore, our data show that systemic soluble TREM2 levels mirror the dynamics of liver infiltrating TREM2+ macrophages and may serve as a circulating marker to track NAFLD progression.

Keywords:  Liver Fibrosis; Metabolic-associated fatty liver disease; Soluble TREM2; Spatial transcriptomics; Steatohepatitis; TREM2+ macrophages

DOI:  https://doi.org/10.1016/j.jhep.2022.06.004
Int J Mol Sci. 2022 Jun 16. pii: 6730. [Epub ahead of print]23(12):

Hypercholesterolemia Negatively Regulates P2X7-Induced Cellular Function in CD4+ and CD8+ T-Cell Subsets from B6 Mice Fed a High-Fat Diet.

Tom Hutteau-Hamel, Amine Mellouk, Nicolas Trainel, Anne-Marie Cassard, Pierre Bobé.

  We have previously showed that plasma membrane cholesterol and GM1 ganglioside content are responsible for the opposite sensitivity of mouse leukemic T cells to ATP. We also reported that the sensitivity of CD4+ and CD8+ T cells to ATP depends on their stage of differentiation. Here, we show that CD4+ and CD8+ T cells from B6 mice express different levels of membrane GM1 and P2X7 but similar levels of cholesterol. Thus, in CD4+ T cells, membrane cholesterol content negatively correlated with ATP/P2X7-induced CD62L shedding but positively correlated with pore formation, phosphatidylserine externalization, and cell death. By contrast, in CD8+ T cells, cholesterol, GM1, and P2X7 levels negatively correlated with all these ATP/P2X7-induced cellular responses. The relationship between cholesterol and P2X7-induced cellular responses was confirmed by modulating cholesterol levels either ex vivo or through a high-fat diet. Membrane cholesterol enrichment ex vivo led to a significant reduction in all P2X7-induced cellular responses in T cells. Importantly, diet-induced hypercholesterolemia in B6 mice was also associated with decreased sensitivity to ATP in CD4+ and CD8+ T cells, highlighting the relationship between cholesterol intake and the amplitudes of P2X7-induced cellular responses in T cells.

Keywords:  P2X7 receptor; T-cell subsets; cholesterol; high fat diet

DOI:  https://doi.org/10.3390/ijms23126730
Immunity. 2022 Jun 18. pii: S1074-7613(22)00239-4. [Epub ahead of print]

Very-low-density lipoprotein receptor-enhanced lipid metabolism in pancreatic stellate cells promotes pancreatic fibrosis.

Xuguang Yang, Jie Chen, Jun Wang, Shuai Ma, Wenxue Feng, Zhihao Wu, Yangyang Guo, Hong Zhou, Wenli Mi, Wei Chen, Bo Yin, Yuli Lin.

  Lipoprotein disorder is a common feature of chronic pancreatitis (CP); however, the relationship between lipoprotein disorder and pancreatic fibrotic environment is unclear. Here, we investigated the occurrence and mechanism of pancreatic stellate cell (PSC) activation by lipoprotein metabolites and the subsequent regulation of type 2 immune responses, as well as the driving force of fibrotic aggressiveness in CP. Single-cell RNA sequencing revealed the heterogeneity of PSCs and identified very-low-density lipoprotein receptor (VLDLR)+ PSCs that were characterized by a higher lipid metabolism. VLDLR promoted intracellular lipid accumulation, followed by interleukin-33 (IL-33) expression and release in PSCs. PSC-derived IL-33 strongly induced pancreatic group 2 innate lymphoid cells (ILC2s) to trigger a type 2 immune response accompanied by the activation of PSCs, eventually leading to fibrosis during pancreatitis. Our findings indicate that VLDLR-enhanced lipoprotein metabolism in PSCs promotes pancreatic fibrosis and highlight a dominant role of IL-33 in this pro-fibrotic cascade.

Keywords:  chronic pancreatitis; group 2 innate lymphoid cell; interleukin-33; pancreatic stellate cells; very-low-density lipoprotein receptor

DOI:  https://doi.org/10.1016/j.immuni.2022.06.001
Cells. 2022 Jun 14. pii: 1916. [Epub ahead of print]11(12):

The Spike Protein of SARS-CoV-2 Impairs Lipid Metabolism and Increases Susceptibility to Lipotoxicity: Implication for a Role of Nrf2.

Vi Nguyen, Yuping Zhang, Chao Gao, Xiaoling Cao, Yan Tian, Wayne Carver, Hippokratis Kiaris, Taixing Cui, Wenbin Tan.

  Coronavirus disease 2019 (COVID-19) patients show lipid metabolic alterations, but the mechanism remains unknown. In this study, we aimed to investigate whether the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impairs lipid metabolism in host cells. We generated a Spike cell line in HEK293 using the pcDNA vector carrying the Spike gene expression cassette. A control cell line was generated using the empty pcDNA vector. Gene expression profiles related to lipid metabolic, autophagic, and ferroptotic pathways were investigated. Palmitic acid (PA)-overload was used to assess lipotoxicity-induced necrosis. As compared with controls, the Spike cells showed a significant increase in lipid depositions in cell membranes as well as dysregulation of expression of a panel of molecules involving lipid metabolism, autophagy, and ferroptosis. The Spike cells showed an upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2), a multifunctional transcriptional factor, in response to PA. Furthermore, the Spike cells exhibited increased necrosis in response to PA-induced lipotoxicity compared to control cells in a time- and dose-dependent manner via ferroptosis, which could be attenuated by the Nrf2 inhibitor trigonelline. We conclude that the Spike protein impairs lipid metabolic and autophagic pathways in host cells, leading to increased susceptibility to lipotoxicity via ferroptosis which can be suppressed by a Nrf2 inhibitor. This data also suggests a central role of Nrf2 in Spike-induced lipid metabolic impairments.

Keywords:  SARS-CoV-2; autophagy; ferroptosis; lipid metabolism; lipotoxicity; spike protein

DOI:  https://doi.org/10.3390/cells11121916
Biomolecules. 2022 May 24. pii: 739. [Epub ahead of print]12(6):

Myristic Acid Supplementation Aggravates High Fat Diet-Induced Adipose Inflammation and Systemic Insulin Resistance in Mice.

Viswanathan Saraswathi, Narendra Kumar, Weilun Ai, Thiyagarajan Gopal, Saumya Bhatt, Edward N Harris, Geoffrey A Talmon, Cyrus V Desouza.

  Saturated fatty acids (SFAs) are considered to be detrimental to human health. One of the SFAs, myristic acid (MA), is known to exert a hypercholesterolemic effect in mice as well as humans. However, its effects on altering adipose tissue (AT) inflammation and systemic insulin resistance (IR) in obesity are still unclear. Here, we sought to determine the effects of a high fat (HF) diet supplemented with MA on obesity-associated metabolic disorders in mice. Wild-type C57BL/6 mice were fed a HF diet in the presence or absence of 3% MA for 12 weeks. Plasma lipids, plasma adipokines, AT inflammation, systemic IR, glucose homeostasis, and hepatic steatosis were assessed. The body weight and visceral adipose tissue (VAT) mass were significantly higher in mice receiving the HF+MA diet compared to HF diet-fed controls. Plasma total cholesterol levels were marginally increased in HF+MA-fed mice compared to controls. Fasting blood glucose was comparable between HF and HF+MA-fed mice. Interestingly, the plasma insulin and HOMA-IR index, a measure of insulin resistance, were significantly higher in HF+MA-fed mice compared to HF controls. Macrophage and inflammatory markers were significantly elevated in the AT and AT-derived stromal vascular cells upon MA feeding. Moreover, the level of circulating resistin, an adipokine promoting insulin resistance, was significantly higher in HF+MA-fed mice compared with HF controls. The insulin tolerance test revealed that the IR was higher in mice receiving the MA supplementation compared to HF controls. Moreover, the glucose tolerance test showed impairment in systemic glucose homeostasis in MA-fed mice. Analyses of liver samples showed a trend towards an increase in liver TG upon MA feeding. However, markers of oxidative stress and inflammation were reduced in the liver of mice fed an MA diet compared to controls. Taken together, our data suggest that chronic administration of MA in diet exacerbates obesity-associated insulin resistance and this effect is mediated in part, via increased AT inflammation and increased secretion of resistin.

Keywords:  adipose inflammation; insulin resistance; myristic acid; obesity; saturated fatty acids

DOI:  https://doi.org/10.3390/biom12060739
Viruses. 2022 May 27. pii: 1158. [Epub ahead of print]14(6):

Metabolomics Analysis of PK-15 Cells with Pseudorabies Virus Infection Based on UHPLC-QE-MS.

Panrao Liu, Danhe Hu, Lili Yuan, Zhengmin Lian, Xiaohui Yao, Zhenbang Zhu, Xiangdong Li.

  Viruses depend on the metabolic mechanisms of the host to support viral replication. We utilize an approach based on ultra-high-performance liquid chromatography/Q Exactive HF-X Hybrid Quadrupole-Orbitrap Mass (UHPLC-QE-MS) to analyze the metabolic changes in PK-15 cells induced by the infections of the pseudorabies virus (PRV) variant strain and Bartha K61 strain. Infections with PRV markedly changed lots of metabolites, when compared to the uninfected cell group. Additionally, most of the differentially expressed metabolites belonged to glycerophospholipid metabolism, sphingolipid metabolism, purine metabolism, and pyrimidine metabolism. Lipid metabolites account for the highest proportion (around 35%). The results suggest that those alterations may be in favor of virion formation and genome amplification to promote PRV replication. Different PRV strains showed similar results. An understanding of PRV-induced metabolic reprogramming will provide valuable information for further studies on PRV pathogenesis and the development of antiviral therapy strategies.

Keywords:  PK-15 cells; UHPLC-QE-MS; metabolomic analysis; pseudorabies virus

DOI:  https://doi.org/10.3390/v14061158
J Hepatol. 2022 Jun 21. pii: S0168-8278(22)00375-0. [Epub ahead of print]

Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease - novel insights into cellular communication circuits.

Moritz Peiseler, Robert Schwabe, Jochen Hampe, Paul Kubes, Mathias Heikenwälder, Frank Tacke.

  Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and emerging as the leading cause of liver cirrhosis, liver transplantation and hepatocellular carcinoma (HCC). NAFLD is a metabolic disease and considered the hepatic manifestation of the metabolic syndrome; however, during the evolution of NAFLD from steatosis to nonalcoholic steatohepatitis (NASH), to more advanced stages of NASH with liver fibrosis, the immune system plays an integral role. Triggers for inflammation are rooted in hepatic (lipid overload, lipotoxicity, oxidative stress) and extrahepatic systems (gut-liver axis, adipose tissue, skeletal muscle), resulting in unique immune-mediated pathomechanisms in NAFLD. In recent years, the implementation of single cell RNA-sequencing (scRNA-seq) and high dimensional multi-omics (proteogenomics, lipidomics) and spatial transcriptomics have tremendously advanced our understanding of the complex heterogeneity of various liver immune cell subsets in health and disease. In NAFLD, several emerging inflammatory mechanisms have been uncovered, including tremendous macrophage heterogeneity, auto-aggressive T cells, the role of unconventional T cells and platelet immune cell interactions potentially yielding novel therapeutics. In this review, we will highlight the recent discoveries related to inflammation in NAFLD, discuss the role of immune cell subsets during the different stages of the disease including disease regression and integrate the multiple systems driving inflammation. We propose a refined concept by which the immune system contributes to all stages of NAFLD and discuss open scientific questions arising from this paradigm shift that need to be unraveled in the coming years, being a basis for reliable diagnosis, prognosis of patients at risk. Finally, we discuss novel therapeutic avenues targeting the multiple triggers of inflammation, including combination therapy via nuclear receptors (FXR agonists, PPAR agonists).

Keywords:  FXR agonists; HCC; Kupffer cells; NAFLD; NASH; PPAR agonists; Single-cell sequencing; cancer immunotherapy; exhausted T cells; immune-mediated liver disease; macrophages; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.jhep.2022.06.012
Front Cell Infect Microbiol. 2022 ;12 915099

The Novel Role of Metabolism-Associated Molecular Patterns in Sepsis.

Xin-Xu Zhu, Wen-Wu Zhang, Cheng-Hua Wu, Shun-Shun Wang, Fang Gao Smith, Sheng-Wei Jin, Pu-Hong Zhang.

  Sepsis, a life-threatening organ dysfunction, is not caused by direct damage of pathogens and their toxins but by the host's severe immune and metabolic dysfunction caused by the damage when the host confronts infection. Previous views focused on the damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), including metabolic proinflammatory factors in sepsis. Recently, new concepts have been proposed to group free fatty acids (FFAs), glucose, advanced glycation end products (AGEs), cholesterol, mitochondrial DNA (mtDNA), oxidized phospholipids (OxPLs), ceramides, and uric acid into metabolism-associated molecular patterns (MAMPs). The concept of MAMPs will bring new guidance to the research and potential treatments of sepsis. Nowadays, sepsis is regarded as closely related to metabolic disorders, and MAMPs play an important role in the pathogenesis and development of sepsis. According to this view, we have explained MAMPs and their possible roles in the pathogenesis of sepsis. Next, we have further explained the specific functions of different types of MAMPs in the metabolic process and their interactional relationship with sepsis. Finally, the therapeutic prospects of MAMPs in sepsis have been summarized.

Keywords:  AGEs; free fatty acids; glucose; metabolism-associated molecular patterns; sepsis

DOI:  https://doi.org/10.3389/fcimb.2022.915099
Redox Biol. 2022 Jun 15. pii: S2213-2317(22)00139-2. [Epub ahead of print]54 102367

STING signaling sensing of DRP1-dependent mtDNA release in kupffer cells contributes to lipopolysaccharide-induced liver injury in mice.

Qin Zhang, Jiayi Wei, Zhuanhua Liu, Xiaoxia Huang, Maomao Sun, Wujiang Lai, Zhenfeng Chen, Jie Wu, Yanjia Chen, Xiaohua Guo, Qiaobing Huang.

  Aberrant pro-inflammatory activation of Kupffer cells (KCs) is strongly involved in the pathogenesis of septic liver injury. Recent evidence indicates the crucial roles of excessive stimulator of interferon genes (STING) signaling activation during sepsis. However, the role of STING signaling in septic liver injury remains unclear. In this study, we demonstrated that STING signaling was markedly activated in KCs isolated from wild type mice after lipopolysaccharide (LPS) treatment. STING deficiency effectively protected liver function, attenuated systemic inflammatory response and decreased mortality in LPS-treated mice, which were aggravated by STING agonist (DMXAA). Importantly, STING signaling activation in KCs contributed to LPS-induced liver injury through promoting hepatocyte death. Mechanistically, STING signaling could be activated by release of mitochondrial DNA (mtDNA) through dynamin-related protein 1 (DRP1)-dependent mitochondrial fission in LPS-treated KCs. Additionally, LPS stimulation enhanced DRP1-dependent mitochondrial ROS production, which promoted the leak of mtDNA into the cytosol and subsequent STING signaling activation in KCs. The in vivo experiments showed that pharmacological inhibition of DRP1 with Mdivi-1 partially prevented the activation of STING signaling in KCs isolated from LPS-challenged mice, as well as alleviated liver injury and inhibited systemic inflammatory response. In summary, our study comprehensively confirmed that STING signaling senses the DRP1-dependent release of mtDNA in KCs and its activation might play a key role in LPS-induced liver injury, which offers new sights and therapeutic targets for management of septic liver injury.

Keywords:  DRP1; Kupffer cell; LPS; Liver injury; STING; mtDNA

DOI:  https://doi.org/10.1016/j.redox.2022.102367
Proc Natl Acad Sci U S A. 2022 Jun 28. 119(26): e2121400119

A small molecule redistributes iron in ferroportin-deficient mice and patient-derived primary macrophages.

Stella Ekaputri, Eun-Kyung Choi, Manuela Sabelli, Luisa Aring, Kelsie J Green, JuOae Chang, Kai Bao, Hak Soo Choi, Shigeki Iwase, Jonghan Kim, Elena Corradini, Antonello Pietrangelo, Martin D Burke, Young Ah Seo.

  Deficiencies of the transmembrane iron-transporting protein ferroportin (FPN1) cause the iron misdistribution that underlies ferroportin disease, anemia of inflammation, and several other human diseases and conditions. A small molecule natural product, hinokitiol, was recently shown to serve as a surrogate transmembrane iron transporter that can restore hemoglobinization in zebrafish deficient in other iron transporting proteins and can increase gut iron absorption in FPN1-deficient flatiron mice. However, whether hinokitiol can restore normal iron physiology in FPN1-deficient animals or primary cells from patients and the mechanisms underlying such targeted activities remain unknown. Here, we show that hinokitiol redistributes iron from the liver to red blood cells in flatiron mice, thereby increasing hemoglobin and hematocrit. Mechanistic studies confirm that hinokitiol functions as a surrogate transmembrane iron transporter to release iron trapped within liver macrophages, that hinokitiol-Fe complexes transfer iron to transferrin, and that the resulting transferrin-Fe complexes drive red blood cell maturation in a transferrin-receptor-dependent manner. We also show in FPN1-deficient primary macrophages derived from patients with ferroportin disease that hinokitiol moves labile iron from inside to outside cells and decreases intracellular ferritin levels. The mobilization of nonlabile iron is accompanied by reductions in intracellular ferritin, consistent with the activation of regulated ferritin proteolysis. These findings collectively provide foundational support for the translation of small molecule iron transporters into therapies for human diseases caused by iron misdistribution.

Keywords:  ferroportin disease; hemoglobinization; hinokitiol; iron misdistribution; iron redistribution

DOI:  https://doi.org/10.1073/pnas.2121400119
Cancer Sci. 2022 Jun 20.

Development of a novel LDHA inhibitor with potent antitumor activity and immune activation.

Mengyan Du, Ting Yu, Qinjinge Zhan, Han Li, Yiping Zou, Meiyu Geng, Tao Meng, Zuoquan Xie.

  Lactate accumulation in tumor microenvironment was shown closely related to tumor growth and immune escape, and suppression of lactate production by inhibiting lactate dehydrogenase (LDHA) has been pursued as a potential novel antitumor strategy, while only a few potent LDHA inhibitors were developed and most of them did not demonstrate potent anti-tumor effect in vivo. To this end, we designed new LDHA inhibitors and obtained a novel potent LDHA inhibitor, ML-05, which inhibited cellular lactate production and inhibited tumor cell proliferation, which associated with the inhibition on ATP production and induction of reactive oxygen species and G1 phase arrest. In mouse B16F10 melanoma model, intratumoral injection with ML-05 significantly reduced lactate production and inhibited tumor growth and released anti-tumor immune response of T cell subsets (Th1, GMZB+ CD8T) in the tumor microenvironment. Moreover, ML-05 treatment combined with PD-1 antibody or stimulator of interferon genes protein (STING) could sensitize the anti-tumor activity for both of them in B16F10 melanoma model. Collectively, we developed a novel potent LDHA inhibitor and demonstrated profound antitumor activity by local administration, which was associated with the activation of antitumor immunity, besides it could sensitize immunotherapies which suggested a great translational value.

Keywords:  Immunity; LDHA inhibitor; Lactate; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1111/cas.15468
Eur J Immunol. 2022 Jun 23.

PTEN is required for human Treg suppression of costimulation in vitro.

Avery J Lam, Manjurul Haque, Kirsten A Ward-Hartstonge, Prakruti Uday, Christine M Wardell, Jana K Gillies, Madeleine Speck, Majid Mojibian, Ramon I Klein Geltink, Megan K Levings.

  Regulatory T cell (Treg) therapy is under clinical investigation for the treatment of transplant rejection, autoimmune disease, and graft-versus-host disease. With the advent of genome editing, attention has turned to reinforcing Treg function for therapeutic benefit. A hallmark of Tregs is dampened activation of PI3K-AKT signalling, of which PTEN is a major negative regulator. Loss-of-function studies of PTEN, however, have not conclusively shown a requirement for PTEN in upholding Treg function and stability. Using CRISPR-based genome editing in human Tregs, we show that PTEN ablation does not cause a global defect in Treg function and stability; rather, it selectively blocks their ability to suppress antigen-presenting cells. PTEN-KO Tregs exhibit elevated glycolytic activity, upregulate FOXP3, maintain a Treg phenotype, and have no discernable defects in lineage stability. Functionally, PTEN is dispensable for human Treg-mediated inhibition of T cell activity in vitro and in vivo, but is required for suppression of costimulatory molecule expression by antigen-presenting cells. These data are the first to define a role for a signalling pathway in controlling a subset of human Treg activity. Moreover, they point to the functional necessity of PTEN-regulated PI3K-AKT activity for optimal human Treg function. This article is protected by copyright. All rights reserved.

Keywords:  CRISPR-Cas9; PI3K-AKT; PTEN; immune regulation; regulatory T cells

DOI:  https://doi.org/10.1002/eji.202249888