bims-imicid 2024-06-16 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024‒06‒16
nineteen papers selected by
Dylan Ryan, University of Cambridge

Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.
Histone Lactylation Drives CD8 T Cell Metabolism and Function.
Intersection of the microbiome and immune metabolism in lupus.
Multi-omic Analysis of Human B-cell Activation Reveals a Key Lysosomal BCAT1 Role in mTOR Hyperactivation by B-cell receptor and TLR9.
Potentiation of the axis involving pentose phosphate pathway/NADPH oxidase/reactive oxygen species drives higher IL-10 production in monocytes of Sub-Saharan Africans.
Using our understanding of interactions between helminth metabolism and host immunity to target worm survival.
Reactive oxygen species regulation by NCF1 governs ferroptosis susceptibility of Kupffer cells to MASH.
The impact of Mycobacterium tuberculosis on the macrophage cholesterol metabolism pathway.
Neutrophil glucose flux as a therapeutic target in antiphospholipid syndrome.
PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway.
Immunomodulation by glucocorticoid-induced leucine zipper in macrophages: enhanced phagocytosis, protection from pyroptosis, and altered mitochondrial function.
Atorvastatin improved ulcerative colitis in association with gut microbiota-derived tryptophan metabolism.
Allergic inflammation triggers dyslipidemia via IgG signalling.
Skeletal muscle mitochondrial dysfunction mediated by Pseudomonas aeruginosa quorum-sensing transcription factor MvfR: reversing effects with anti-MvfR and mitochondrial-targeted compounds.
Linking IL-10 signaling with lipid metabolic programs in macrophages: dysregulated ceramide homeostasis drives colitis.
Serine Depletion Promotes Anti-Tumor Immunity by Activating Mitochondrial DNA-mediated cGAS-STING Signaling.
Injectable butyrate-prodrug micelles induce long-acting immune modulation and prevent autoimmune arthritis in mice.
Single-cell analysis identifies conserved features of immune dysfunction in simulated microgravity and spaceflight.
Targeting glucose metabolism with dichloroacetate (DCA) reduces zika virus replication in brain cortical progenitors at different stages of maturation.

Nature. 2024 Jun 12.

Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.

Jackie E Bader, Melissa M Wolf, Gian Luca Lupica-Tondo, Matthew Z Madden, Bradley I Reinfeld, Emily N Arner, Emma S Hathaway, KayLee K Steiner, Gabriel A Needle, Zaid Hatem, Madelyn D Landis, Eden E Faneuff, Amondrea Blackman, Elysa M Wolf, Matthew A Cottam, Xiang Ye, Madison E Bates, Kyra Smart, Wenjun Wang, Laura V Pinheiro, Anthos Christofides, DuPreez Smith, Vassiliki A Boussiotis, Scott M Haake, Kathryn E Beckermann, Kathryn E Wellen, Cynthia A Reinhart-King, C Henrique Serezani, Cheng-Han Lee, Christa Aubrey, Heidi Chen, W Kimryn Rathmell, Alyssa H Hasty, Jeffrey C Rathmell.

Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can in some cases enhance survival3-5 and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells6-8. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-19-12. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8+ T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity.

DOI: https://doi.org/10.1038/s41586-024-07529-3
bioRxiv. 2024 Jun 01. pii: 2023.08.25.554830. [Epub ahead of print]

Histone Lactylation Drives CD8 T Cell Metabolism and Function.

Deblina Raychaudhuri, Pratishtha Singh, Mercedes Hennessey, Bidisha Chakraborty, Aminah J Tannir, Abel Trujillo-Ocampo, Jin Seon Im, Sangeeta Goswami.

The activation and functional differentiation of CD8 T cells are linked to metabolic pathways that result in the production of lactate. Lactylation is a lactate-derived histone post-translational modification (hPTM); however, the relevance of histone lactylation in the context of CD8 T cell activation and function is not known. Here, we show the enrichment of H3K18-lactylation (H3K18la) and H3K9-lactylation (H3K9la) in human and murine CD8 T cells which act as transcription initiators of key genes regulating CD8 T cell phenotype and function. Further, we note distinct impacts of H3K18la and H3K9la on CD8 T cell subsets linked to their specific metabolic profiles. Importantly, we demonstrate that modulation of H3K18la and H3K9la by targeting metabolic and epigenetic pathways regulates CD8 T cell effector function including anti-tumor immunity in preclinical models. Overall, our study uncovers the unique contributions of H3K18la and H3K9la in modulating CD8 T cell phenotype and function intricately associated with metabolic state.

DOI: https://doi.org/10.1101/2023.08.25.554830
Immunol Rev. 2024 Jun 14.

Intersection of the microbiome and immune metabolism in lupus.

Abigail Castellanos Garcia, Natalie Six, Longhuan Ma, Laurence Morel.

  Systemic lupus erythematosus is a complex autoimmune disease resulting from a dysregulation of the immune system that involves gut dysbiosis and an altered host cellular metabolism. This review highlights novel insights and expands on the interactions between the gut microbiome and the host immune metabolism in lupus. Pathobionts, invasive pathogens, and even commensal microbes, when in dysbiosis, can all trigger and modulate immune responses through metabolic reprogramming. Changes in the microbiota's global composition or individual taxa may trigger a cascade of metabolic changes in immune cells that may, in turn, reprogram their functions. Factors contributing to dysbiosis include changes in intestinal hypoxia, competition for glucose, and limited availability of essential nutrients, such as tryptophan and metal ions, all of which can be driven by host metabolism changes. Conversely, the accumulation of some host metabolites, such as itaconate, succinate, and free fatty acids, could further influence the microbial composition and immune responses. Overall, mounting evidence supports a bidirectional relationship between host immunometabolism and the microbiota in lupus pathogenesis.

Keywords:  glucose; lupus; metabolism; microbiome; mitochondria; tryptophan

DOI:  https://doi.org/10.1111/imr.13360
Res Sq. 2024 May 30. pii: rs.3.rs-4413958. [Epub ahead of print]

Multi-omic Analysis of Human B-cell Activation Reveals a Key Lysosomal BCAT1 Role in mTOR Hyperactivation by B-cell receptor and TLR9.

Benjamin Gewurz, Rui Guo, Matthew Lim, Hardik Shah, Joao Paulo, Yuchen Zhang, Haopeng Yang, Liang Wei Wang, Daniel Strebinger, Nicolas Smith, Meng Li, Merrin Leong, Michael Lutchenkov, Jin-Hua Liang, Zhixuan Li, Yin Wang, Rishi Puri, Ari Melnick, Michael Green, John Asara, Adonia Papathanassiu, Steven Gygi, Vamsi Mootha.

B-lymphocytes play major adaptive immune roles, producing antibody and driving T-cell responses. However, how immunometabolism networks support B-cell activation and differentiation in response to distinct receptor stimuli remains incompletely understood. To gain insights, we systematically investigated acute primary human B-cell transcriptional, translational and metabolomic responses to B-cell receptor (BCR), Toll-like receptor 9 (TLR9), CD40-ligand (CD40L), interleukin-4 (IL4) or combinations thereof. T-independent BCR/TLR9 co-stimulation, which drives malignant and autoimmune B-cell states, jointly induced PD-L1 plasma membrane expression, supported by NAD metabolism and oxidative phosphorylation. BCR/TLR9 also highly induced the transaminase BCAT1, which localized to lysosomal membranes to support branched chain amino acid synthesis and mTORC1 hyperactivation. BCAT1 inhibition blunted BCR/TLR9, but not CD40L/IL4-triggered B-cell proliferation, IL10 expression and BCR/TLR pathway-driven lymphoma xenograft outgrowth. These results provide a valuable resource, reveal receptor-mediated immunometabolism remodeling to support key B-cell phenotypes including PD-L1 checkpoint signaling, and identify BCAT1 as a novel B-cell therapeutic target.

DOI: https://doi.org/10.21203/rs.3.rs-4413958/v1
Eur J Immunol. 2024 Jun 14. e2451029

Potentiation of the axis involving pentose phosphate pathway/NADPH oxidase/reactive oxygen species drives higher IL-10 production in monocytes of Sub-Saharan Africans.

Madeleine Eunice Betouke Ongwe, Yoanne D Mouwenda, Mikhael D Manurung, Graham Heieis, Shohreh Azimi, Ayola A Adegnika, Peter G Kremsner, Taco W Kuijpers, Maria Yazdanbakhsh, Bart Everts.

  Cellular metabolism is a key determinant of immune cell function. Here we found that CD14+ monocytes from Sub-Saharan Africans produce higher levels of IL-10 following TLR-4 stimulation and are bioenergetically distinct from monocytes from Europeans. Through metabolomic profiling, we identified the higher IL-10 production to be driven by increased baseline production of NADPH oxidase-dependent reactive oxygen species, supported by enhanced pentose phosphate pathway activity. Together, these data indicate that NADPH oxidase-derived ROS is a metabolic checkpoint in monocytes that governs their inflammatory profile and uncovers a metabolic basis for immunological differences across geographically distinct populations.

Keywords:  IL‐10; Monocytes; NADPH‐oxidase; Pentose phosphate pathway; ROS

DOI:  https://doi.org/10.1002/eji.202451029
Trends Parasitol. 2024 Jun 08. pii: S1471-4922(24)00135-1. [Epub ahead of print]

Using our understanding of interactions between helminth metabolism and host immunity to target worm survival.

Ella K Reed, Katherine A Smith.

  Helminths can adapt to environmental conditions in the host, utilising anaerobic processes like fermentation and malate dismutation to produce energy from carbohydrate. Although targeting carbohydrate metabolism is an established therapeutic strategy to combat helminth infection, questions remain over the metabolic pathways they employ as adults to survive and evade host immunity. Helminths also use amino acid, polyunsaturated fatty acid (PUFA), and cholesterol metabolism, a possible strategy favouring the production of immunomodulatory compounds that may influence survival in the host. Here, we discuss the significance of these differing metabolic pathways and whether targeting of helminth metabolic pathways may allow for the development of novel anthelmintics.

Keywords:  anthelmintics; helminths; lipids; metabolism

DOI:  https://doi.org/10.1016/j.pt.2024.05.006
Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00184-0. [Epub ahead of print]

Reactive oxygen species regulation by NCF1 governs ferroptosis susceptibility of Kupffer cells to MASH.

Jing Zhang, Yu Wang, Meiyang Fan, Yanglong Guan, Wentao Zhang, Fumeng Huang, Zhengqiang Zhang, Xiaomeng Li, Bingyu Yuan, Wenbin Liu, Manman Geng, Xiaowei Li, Jing Xu, Congshan Jiang, Wenjuan Zhao, Feng Ye, Wenhua Zhu, Liesu Meng, Shemin Lu, Rikard Holmdahl.

  Impaired self-renewal of Kupffer cells (KCs) leads to inflammation in metabolic dysfunction-associated steatohepatitis (MASH). Here, we identify neutrophil cytosolic factor 1 (NCF1) as a critical regulator of iron homeostasis in KCs. NCF1 is upregulated in liver macrophages and dendritic cells in humans with metabolic dysfunction-associated steatotic liver disease and in MASH mice. Macrophage NCF1, but not dendritic cell NCF1, triggers KC iron overload, ferroptosis, and monocyte-derived macrophage infiltration, thus aggravating MASH progression. Mechanistically, elevated oxidized phospholipids induced by macrophage NCF1 promote Toll-like receptor (TLR4)-dependent hepatocyte hepcidin production, leading to increased KC iron deposition and subsequent KC ferroptosis. Importantly, the human low-functional polymorphic variant NCF190H alleviates KC ferroptosis and MASH in mice. In conclusion, macrophage NCF1 impairs iron homeostasis in KCs by oxidizing phospholipids, triggering hepatocyte hepcidin release and KC ferroptosis in MASH, highlighting NCF1 as a therapeutic target for improving KC fate and limiting MASH progression.

Keywords:  Kupffer cells; NCF1; ferroptosis; hepatocytes; iron deposition; lipid peroxidation; macrophages; metabolic dysfunction-associated steatohepatitis; oxidized phospholipids; reactive oxygen species

DOI:  https://doi.org/10.1016/j.cmet.2024.05.008
Front Immunol. 2024 ;15 1402024

The impact of Mycobacterium tuberculosis on the macrophage cholesterol metabolism pathway.

Zhanpeng Chen, Xingxing Kong, Quan Ma, Jinyun Chen, Yuqin Zeng, Huazhen Liu, Xiaomin Wang, Shuihua Lu.

  Mycobacterium tuberculosis (Mtb) is an intracellular pathogen capable of adapting and surviving within macrophages, utilizing host nutrients for its growth and replication. Cholesterol is the main carbon source during the infection process of Mtb. Cholesterol metabolism in macrophages is tightly associated with cell functions such as phagocytosis of pathogens, antigen presentation, inflammatory responses, and tissue repair. Research has shown that Mtb infection increases the uptake of low-density lipoprotein (LDL) and cholesterol by macrophages, and enhances de novo cholesterol synthesis in macrophages. Excessive cholesterol is converted into cholesterol esters, while the degradation of cholesterol esters in macrophages is inhibited by Mtb. Furthermore, Mtb infection suppresses the expression of ATP-binding cassette (ABC) transporters in macrophages, impeding cholesterol efflux. These alterations result in the massive accumulation of cholesterol in macrophages, promoting the formation of lipid droplets and foam cells, which ultimately facilitates the persistent survival of Mtb and the progression of tuberculosis (TB), including granuloma formation, tissue cavitation, and systemic dissemination. Mtb infection may also promote the conversion of cholesterol into oxidized cholesterol within macrophages, with the oxidized cholesterol exhibiting anti-Mtb activity. Recent drug development has discovered that reducing cholesterol levels in macrophages can inhibit the invasion of Mtb into macrophages and increase the permeability of anti-tuberculosis drugs. The development of drugs targeting cholesterol metabolic pathways in macrophages, as well as the modification of existing drugs, holds promise for the development of more efficient anti-tuberculosis medications.

Keywords:  MTB; TB; cholesterol metabolism; foam cell; lipid droplet; macrophages; oxidized cholesterol

DOI:  https://doi.org/10.3389/fimmu.2024.1402024
J Clin Invest. 2024 Jun 13. pii: e169893. [Epub ahead of print]

Neutrophil glucose flux as a therapeutic target in antiphospholipid syndrome.

Ajay Tambralli, Alyssa Harbaugh, Somanathapura K NaveenKumar, Megan D Radyk, Christine E Rysenga, Kaitlyn Sabb, Julia M Hurley, Gautam J Sule, Srilakshmi Yalavarthi, Shanea K Estes, Claire Hoy, Tristin Smith, Cyrus Sarosh, Jacqueline A Madison, Jordan K Schaefer, Suman L Sood, Yu Zuo, Amr H Sawalha, Costas A Lyssiotis, Jason S Knight.

  Neutrophil hyperactivity and neutrophil extracellular trap release (NETosis) appear to play important roles in the pathogenesis of the thromboinflammatory autoimmune disease known as antiphospholipid syndrome (APS). The understanding of neutrophil metabolism has advanced tremendously in the past decade, and accumulating evidence suggests that a variety of metabolic pathways guide neutrophil activities in health and disease. Our previous work characterizing the transcriptome of APS neutrophils revealed that genes related to glycolysis, glycogenolysis, and the pentose phosphate pathway (PPP) were significantly upregulated. Here, we found that APS patient neutrophils used glycolysis more avidly than healthy control neutrophils, especially when the neutrophils were from APS patients with a history of microvascular disease. In vitro, inhibiting either glycolysis or the PPP tempered phorbol myristate acetate- and APS IgG-induced NETosis, but not NETosis triggered by a calcium ionophore. In mice, inhibiting either glycolysis or the PPP reduced neutrophil reactive oxygen species production and suppressed APS IgG-induced NETosis ex vivo. When APS-associated thrombosis was evaluated in mice, inhibiting either glycolysis or the PPP markedly suppressed thrombosis and circulating NET remnants. In summary, these data identify a potential role for restraining neutrophil glucose flux in the treatment of APS.

Keywords:  Autoimmune diseases; Autoimmunity; Glucose metabolism; Neutrophils

DOI:  https://doi.org/10.1172/JCI169893
J Exp Med. 2024 Jul 01. pii: e20221721. [Epub ahead of print]221(7):

PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway.

Jonathan J Hodgins, John Abou-Hamad, Colin Edward O'Dwyer, Ash Hagerman, Edward Yakubovich, Christiano Tanese de Souza, Marie Marotel, Ariel Buchler, Saleh Fadel, Maria M Park, Claire Fong-McMaster, Mathieu F Crupi, Olivia Joan Makinson, Reem Kurdieh, Reza Rezaei, Harkirat Singh Dhillon, Carolina S Ilkow, John C Bell, Mary-Ellen Harper, Benjamin H Rotstein, Rebecca C Auer, Barbara C Vanderhyden, Luc A Sabourin, Marie-Claude Bourgeois-Daigneault, David P Cook, Michele Ardolino.

While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 promoted a metabolic shift characterized by enhanced glycolysis rate that resulted in increased lactate production. In turn, lactate inhibited type I IFN responses. In addition to adding mechanistic insight into PD-L1 intrinsic function, our results will also help guide the numerous ongoing efforts to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.

DOI: https://doi.org/10.1084/jem.20221721
Front Immunol. 2024 ;15 1396827

Immunomodulation by glucocorticoid-induced leucine zipper in macrophages: enhanced phagocytosis, protection from pyroptosis, and altered mitochondrial function.

Thierry M Legroux, Hanna S Schymik, Gilles Gasparoni, Saeed Mohammadi, Jörn Walter, Claude Libert, Britta Diesel, Jessica Hoppstädter, Alexandra K Kiemer.

  Glucocorticoids, which have long served as fundamental therapeutics for diverse inflammatory conditions, are still widely used, despite associated side effects limiting their long-term use. Among their key mediators is glucocorticoid-induced leucine zipper (GILZ), recognized for its anti-inflammatory and immunosuppressive properties. Here, we explore the immunomodulatory effects of GILZ in macrophages through transcriptomic analysis and functional assays. Bulk RNA sequencing of GILZ knockout and GILZ-overexpressing macrophages revealed significant alterations in gene expression profiles, particularly impacting pathways associated with the inflammatory response, phagocytosis, cell death, mitochondrial function, and extracellular structure organization activity. GILZ-overexpression enhances phagocytic and antibacterial activity against Salmonella typhimurium and Escherichia coli, potentially mediated by increased nitric oxide production. In addition, GILZ protects macrophages from pyroptotic cell death, as indicated by a reduced production of reactive oxygen species (ROS) in GILZ transgenic macrophages. In contrast, GILZ KO macrophages produced more ROS, suggesting a regulatory role of GILZ in ROS-dependent pathways. Additionally, GILZ overexpression leads to decreased mitochondrial respiration and heightened matrix metalloproteinase activity, suggesting its involvement in tissue remodeling processes. These findings underscore the multifaceted role of GILZ in modulating macrophage functions and its potential as a therapeutic target for inflammatory disorders, offering insights into the development of novel therapeutic strategies aimed at optimizing the benefits of glucocorticoid therapy while minimizing adverse effects.

Keywords:  RNA-seq; extracellular matrix; iNOS; immunometabolism; lipopolysaccharide (LPS); reactive oxygen species (ROS)

DOI:  https://doi.org/10.3389/fimmu.2024.1396827
Life Sci. 2024 Jun 07. pii: S0024-3205(24)00380-1. [Epub ahead of print] 122790

Atorvastatin improved ulcerative colitis in association with gut microbiota-derived tryptophan metabolism.

Yidan Gou, Shijiao Cai, YanYan Chen, Xiaoran Hou, Jing Zhang, Chongwen Bi, Peng Gu, Miao Yang, Hanxu Zhang, Weilong Zhong, Hengjie Yuan.

  AIMS: Atorvastatin is a commonly used cholesterol-lowering drug that possesses non-canonical anti-inflammatory properties. However, the precise mechanism underlying its anti-inflammatory effects remains unclear.MATERIALS AND METHODS: The acute phase of ulcerative colitis (UC) was induced using a 5 % dextran sulfate sodium (DSS) solution for 7 consecutive days and administrated with atorvastatin (10 mg/kg) from day 3 to day 7. mRNA-seq, histological pathology, and inflammatory response were determined. Intestinal microbiota alteration, tryptophan, and its metabolites were analyzed through 16S rRNA sequencing and untargeted metabolomics.
KEY FINDINGS: Atorvastatin relieved the DSS-induced UC in mice, as evidenced by weight loss, colon length, disease activity index score and pathological staining. Atorvastatin treatment reduced the level of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Atorvastatin also relieved the intestinal microbiota disorder caused by UC and decreased the proliferation of pernicious microbiota such as Akkermansia and Bacteroides. Atorvastatin dramatically altered tryptophan metabolism and increased the fecal contents of tryptophan, indolelactic acid (ILA), and indole-3-acetic acid (IAA). Furthermore, atorvastatin enhanced the expression level of aryl hydrocarbon receptor (AhR) and interleukin-22 (IL-22) and further promoted the expression level of intestinal tight junction proteins, such as ZO-1 and occluding, in colitis mice with colitis.
SIGNIFICANCE: These findings indicated that atorvastatin could alleviate UC by regulating intestinal flora disorders, promoting microbial tryptophan metabolism, and repairing the intestinal barrier.

Keywords:  Aryl hydrocarbon receptor; Atorvastatin; Intestinal microbiota; Tryptophan metabolism; Ulcerative colitis

DOI:  https://doi.org/10.1016/j.lfs.2024.122790
Allergy. 2024 Jun 12.

Allergic inflammation triggers dyslipidemia via IgG signalling.

Nieves Fernández-Gallego, Raquel Castillo-González, Lucía Moreno-Serna, Antonio J García-Cívico, Elisa Sánchez-Martínez, Celia López-Sanz, Ana Luiza Fontes, Lígia L Pimentel, Ana Gradillas, David Obeso, René Neuhaus, Marta Ramírez-Huesca, Ignacio Ruiz-Fernández, Emilio Nuñez-Borque, Yolanda R Carrasco, Borja Ibáñez, Pilar Martín, Carlos Blanco, Coral Barbas, Domingo Barber, Luis M Rodríguez-Alcalá, Alma Villaseñor, Vanesa Esteban, Francisco Sánchez-Madrid, Rodrigo Jiménez-Saiz.

  BACKGROUND: Allergic diseases begin early in life and are often chronic, thus creating an inflammatory environment that may precede or exacerbate other pathologies. In this regard, allergy has been associated to metabolic disorders and with a higher risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood.METHODS: We used a murine model of allergy and atherosclerosis, different diets and sensitization methods, and cell-depleting strategies to ascertain the contribution of acute and late phase inflammation to dyslipidemia. Untargeted lipidomic analyses were applied to define the lipid fingerprint of allergic inflammation at different phases of allergic pathology. Expression of genes related to lipid metabolism was assessed in liver and adipose tissue at different times post-allergen challenge. Also, changes in serum triglycerides (TGs) were evaluated in a group of 59 patients ≥14 days after the onset of an allergic reaction.
RESULTS: We found that allergic inflammation induces a unique lipid signature that is characterized by increased serum TGs and changes in the expression of genes related to lipid metabolism in liver and adipose tissue. Alterations in blood TGs following an allergic reaction are independent of T-cell-driven late phase inflammation. On the contrary, the IgG-mediated alternative pathway of anaphylaxis is sufficient to induce a TG increase and a unique lipid profile. Lastly, we demonstrated an increase in serum TGs in 59 patients after undergoing an allergic reaction.
CONCLUSION: Overall, this study reveals that IgG-mediated allergic inflammation regulates lipid metabolism.

Keywords:  IgG; allergic inflammation; cardiovascular risk; dyslipidemia; lipidomics; metabolism

DOI:  https://doi.org/10.1111/all.16187
mBio. 2024 Jun 11. e0129224

Skeletal muscle mitochondrial dysfunction mediated by Pseudomonas aeruginosa quorum-sensing transcription factor MvfR: reversing effects with anti-MvfR and mitochondrial-targeted compounds.

Shifu Aggarwal, Vijay Singh, Arijit Chakraborty, Sujin Cha, Alexandra Dimitriou, Claire de Crescenzo, Olivia Izikson, Lucy Yu, Roberto Plebani, A Aria Tzika, Laurence G Rahme.

  Sepsis and chronic infections with Pseudomonas aeruginosa, a leading "ESKAPE" bacterial pathogen, are associated with increased morbidity and mortality and skeletal muscle atrophy. The actions of this pathogen on skeletal muscle remain poorly understood. In skeletal muscle, mitochondria serve as a crucial energy source, which may be perturbed by infection. Here, using the well-established backburn and infection model of murine P. aeruginosa infection, we deciphered the systemic impact of the quorum-sensing transcription factor MvfR (multiple virulence factor regulator) by interrogating, 5 days post-infection, its effect on mitochondrial-related functions in the gastrocnemius skeletal muscle and the outcome of the pharmacological inhibition of MvfR function and that of the mitochondrial-targeted peptide, Szeto-Schiller 31 (SS-31). Our findings show that the MvfR perturbs adenosine triphosphate generation, oxidative phosphorylation, and antioxidant response, elevates the production of reactive oxygen species, and promotes oxidative damage of mitochondrial DNA in the gastrocnemius muscle of infected mice. These impairments in mitochondrial-related functions were corroborated by the alteration of key mitochondrial proteins involved in electron transport, mitochondrial biogenesis, dynamics and quality control, and mitochondrial uncoupling. Pharmacological inhibition of MvfR using the potent anti-MvfR lead, D88, we developed, or the mitochondrial-targeted peptide SS-31 rescued the MvfR-mediated alterations observed in mice infected with the wild-type strain PA14. Our study provides insights into the actions of MvfR in orchestrating mitochondrial dysfunction in the skeletal murine muscle, and it presents novel therapeutic approaches for optimizing clinical outcomes in affected patients.IMPORTANCE: Skeletal muscle, pivotal for many functions in the human body, including breathing and protecting internal organs, contains abundant mitochondria essential for maintaining cellular homeostasis during infection. The effect of Pseudomonas aeruginosa (PA) infections on skeletal muscle remains poorly understood. Our study delves into the role of a central quorum-sensing transcription factor, multiple virulence factor regulator (MvfR), that controls the expression of multiple acute and chronic virulence functions that contribute to the pathogenicity of PA. The significance of our study lies in the role of MvfR in the metabolic perturbances linked to mitochondrial functions in skeletal muscle and the effectiveness of the novel MvfR inhibitor and the mitochondrial-targeted peptide SS-31 in alleviating the mitochondrial disturbances caused by PA in skeletal muscle. Inhibiting MvfR or interfering with its effects can be a potential therapeutic strategy to curb PA virulence.

Keywords:  ATP; MvfR; PA14; PqsR; Pseudomonas aeruginosa; ROS; bioenergetics; infection; metabolism; mitochondrial dysfunction; mitochondrion; mitophagy; oxidative phosphorylation; quorum sensing; skeletal muscle

DOI:  https://doi.org/10.1128/mbio.01292-24
Signal Transduct Target Ther. 2024 Jun 08. 9(1): 156

Linking IL-10 signaling with lipid metabolic programs in macrophages: dysregulated ceramide homeostasis drives colitis.

Imke Atreya, Markus F Neurath.

DOI: https://doi.org/10.1038/s41392-024-01864-7
Cancer Res. 2024 Jun 11.

Serine Depletion Promotes Anti-Tumor Immunity by Activating Mitochondrial DNA-mediated cGAS-STING Signaling.

Suchandrima Saha, Monisankar Ghosh, Jinyu Li, Asher Wen, Lorenzo Galluzzi, Luis A Martinez, David C Montrose.

Serine is critical for supporting cancer metabolism, and depriving malignant cells of this non-essential amino acid exerts anti-neoplastic effects, in large part, through disrupting metabolic pathways. Given the intricate relationship between cancer metabolism and the immune system, the metabolic defects imposed by serine deprivation might impact tumor-targeting immunity. Here, we demonstrated that restricting endogenous and exogenous sources of serine in colorectal cancer (CRC) cells results in mitochondrial dysfunction, leading to mitochondrial DNA (mtDNA) accumulation in the cytosol and consequent cGAS-STING1-driven type I interferon (IFN) secretion. Depleting mtDNA or blocking its release attenuated cGAS-STING1 activation during serine deprivation. In vivo studies revealed that serine deprivation limits tumor growth, accompanied by enhanced type I IFN signaling and intratumoral infiltration of immune effector cells. Notably, the tumor-suppressive and immune-enhancing effects of serine restriction were impaired by T cell depletion and IFN receptor blockade. Moreover, disrupting cGAS-STING1 signaling in CRC cells limited the immunostimulatory and tumor-suppressive effects of serine deprivation. Lastly, serine depletion increased the sensitivity of tumors to an immune checkpoint inhibitor targeting PD-1. Taken together, these findings reveal a role for serine as a suppressor of anti-tumor immunity, suggesting that serine deprivation may be employed to enhance tumor immunogenicity and improve responsiveness to immune checkpoint inhibitors.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-1788
J Control Release. 2024 Jun 12. pii: S0168-3659(24)00375-4. [Epub ahead of print]

Injectable butyrate-prodrug micelles induce long-acting immune modulation and prevent autoimmune arthritis in mice.

Shijie Cao, Erica Budina, Ruyi Wang, Matthew Sabados, Anish Mukherjee, Ani Solanki, Mindy Nguyen, Kevin Hultgren, Arjun Dhar, Jeffrey A Hubbell.

  Short chain fatty acid (SCFAs), such as butyrate, have shown promising therapeutic potential due to their immunomodulatory effects, particularly in maintaining immune homeostasis. However, the clinical application of SCFAs is limited by the need for frequent and high oral dosages. Rheumatoid arthritis (RA) is characterized by aberrant activation of peripheral T cells and myeloid cells. In this study, we aimed to deliver butyrate directly to the lymphatics using a polymeric micelle-based butyrate prodrug to induce long-lasting immunomodulatory effects. Notably, negatively charged micelles (Neg-ButM) demonstrated superior efficacy in targeting the lymphatics following subcutaneous (s.c.) administration and were retained in the draining lymph nodes, spleen, and liver for over one month. In the collagen antibody-induced arthritis (CAIA) mouse model of RA, only two s.c. injections of Neg-ButM successfully prevented disease onset and promoted tolerogenic phenotypes in T cells and myeloid cells, both locally and systemically. These results underscore the potential of this strategy in managing inflammatory autoimmune diseases by directly modulating immune responses via lymphatic delivery.

Keywords:  Rheumatoid arthritis; butyrate; immune modulation; lymphatic targeting; polymeric micelles

DOI:  https://doi.org/10.1016/j.jconrel.2024.06.027
Nat Commun. 2024 Jun 11. 15(1): 4795

Single-cell analysis identifies conserved features of immune dysfunction in simulated microgravity and spaceflight.

Fei Wu, Huixun Du, Eliah Overbey, JangKeun Kim, Priya Makhijani, Nicolas Martin, Chad A Lerner, Khiem Nguyen, Jordan Baechle, Taylor R Valentino, Matias Fuentealba, Juliet M Bartleson, Heather Halaweh, Shawn Winer, Cem Meydan, Francine Garrett-Bakelman, Nazish Sayed, Simon Melov, Masafumi Muratani, Akos A Gerencser, Herbert G Kasler, Afshin Beheshti, Christopher E Mason, David Furman, Daniel A Winer.

Microgravity is associated with immunological dysfunction, though the mechanisms are poorly understood. Here, using single-cell analysis of human peripheral blood mononuclear cells (PBMCs) exposed to short term (25 hours) simulated microgravity, we characterize altered genes and pathways at basal and stimulated states with a Toll-like Receptor-7/8 agonist. We validate single-cell analysis by RNA sequencing and super-resolution microscopy, and against data from the Inspiration-4 (I4) mission, JAXA (Cell-Free Epigenome) mission, Twins study, and spleens from mice on the International Space Station. Overall, microgravity alters specific pathways for optimal immunity, including the cytoskeleton, interferon signaling, pyroptosis, temperature-shock, innate inflammation (e.g., Coronavirus pathogenesis pathway and IL-6 signaling), nuclear receptors, and sirtuin signaling. Microgravity directs monocyte inflammatory parameters, and impairs T cell and NK cell functionality. Using machine learning, we identify numerous compounds linking microgravity to immune cell transcription, and demonstrate that the flavonol, quercetin, can reverse most abnormal pathways. These results define immune cell alterations in microgravity, and provide opportunities for countermeasures to maintain normal immunity in space.

DOI: https://doi.org/10.1038/s41467-023-42013-y
Antiviral Res. 2024 Jun 06. pii: S0166-3542(24)00142-6. [Epub ahead of print]228 105933

Targeting glucose metabolism with dichloroacetate (DCA) reduces zika virus replication in brain cortical progenitors at different stages of maturation.

Javier Gilbert-Jaramillo, Thamil Vaani Komarasamy, Vinod Rmt Balasubramaniam, Lisa C Heather, William S James.

The underlying threat of new Zika virus (ZIKV) outbreaks remains, as no vaccines or therapies have yet been developed. In vitro research has shown that glycolysis is a key factor to enable sustained ZIKV replication in neuroprogenitors. However, neither in vivo nor clinical investigation of glycolytic modulators as potential therapeutics for ZIKV-related fetal abnormalities has been conducted. Accordingly, we tested the therapeutic potential of metabolic modulators in relevant in vitro systems comprising two pools of neuroprogenitors (NPCs), which resemble early and late stages of pregnancy. Effective doses of metabolic modulators [3.0 μM] dimethyl fumarate (DMF), [3.2 mM] dichloroacetate (DCA), and [6.3 μM] VER-246608 were determined for these cells by their effect on lactate release, pyruvate dehydrogenase (PDH) activity and cell survival. The drugs were used in a 24h pre-treatment and kept throughout ZIKV infection of NPCs. Drug effects and ZIKV replication were assessed at 24- and 56-h post-infection. In early NPCs treated with DMF, DCA and VER-246608, there was a significant reduction in the extracellular release of ZIKV potentially by PDH-mediated increased mitochondrial oxidation of glucose. Out of the three drugs, only DCA was observed to reduce viral replication in late NPCs treated with DCA. Altogether, our findings suggest that reduction of anaerobic glycolysis could be of therapeutic potential against ZIKV-related fetal abnormalities and that clinical translation should consider the use of specific glycolytic modulators over different trimesters.

DOI: https://doi.org/10.1016/j.antiviral.2024.105933