bims-imicid 2024-08-04 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024‒08‒04
thirteen papers selected by
Dylan Ryan, University of Cambridge

Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation.
Impaired fatty acid import or catabolism in macrophages restricts intracellular growth of Mycobacterium tuberculosis.
Endogenously produced itaconate negatively regulates innate-driven cytokine production and drives global ubiquitination in human macrophages.
Remodeling of T-cell mitochondrial metabolism to treat autoimmune diseases.
Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice.
CPT1A-IL-10-mediated macrophage metabolic and phenotypic alterations ameliorate acute lung injury.
Bile acids attenuate hepatic inflammation during ischemia/reperfusion injury.
Hypoxia activates macrophage-NLRP3 inflammasome promoting atherosclerosis via PFKFB3-driven glycolysis.
Glycolytic enzyme PGK1 promotes M1 macrophage polarization and induces pyroptosis of acute lung injury via regulation of NLRP3.
Mitochondrial DNA Programs Lactylation of cGAS to Induce IFN Responses in Patients with Systemic Lupus Erythematosus.
Hepatic macrophage niche: a bridge between HBV-mediated metabolic changes with intrahepatic inflammation.
Glycolysis Changes in Alloreactive Memory B Cells in Highly Sensitized Kidney Transplant Recipients Undergonig Desensitization Therapy.
Adenosine triggers early astrocyte reactivity that provokes microglial responses and drives the pathogenesis of sepsis-associated encephalopathy in mice.

Nat Commun. 2024 Jul 31. 15(1): 6438

Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation.

Meiyue Wang, Heinrich Flaswinkel, Abhinav Joshi, Matteo Napoli, Sergi Masgrau-Alsina, Julia M Kamper, Antonia Henne, Alexander Heinz, Marleen Berouti, Niklas A Schmacke, Karsten Hiller, Elisabeth Kremmer, Benedikt Wefers, Wolfgang Wurst, Markus Sperandio, Jürgen Ruland, Thomas Fröhlich, Veit Hornung.

Innate immune responses are linked to key metabolic pathways, yet the proximal signaling events that connect these systems remain poorly understood. Here we show that phosphofructokinase 1, liver type (PFKL), a rate-limiting enzyme of glycolysis, is phosphorylated at Ser775 in macrophages following several innate stimuli. This phosphorylation increases the catalytic activity of PFKL, as shown by biochemical assays and glycolysis monitoring in cells expressing phosphorylation-defective PFKL variants. Using a genetic mouse model in which PFKL Ser775 phosphorylation cannot take place, we observe that upon activation, glycolysis in macrophages is lower than in the same cell population of wild-type animals. Consistent with their higher glycolytic activity, wild-type cells have higher levels of HIF1α and IL-1β than PfklS775A/S775A after LPS treatment. In an in vivo inflammation model, PfklS775A/S775A mice show reduced levels of MCP-1 and IL-1β. Our study thus identifies a molecular link between innate immune activation and early induction of glycolysis.

DOI: https://doi.org/10.1038/s41467-024-50104-7
bioRxiv. 2024 Jul 23. pii: 2024.07.22.604660. [Epub ahead of print]

Impaired fatty acid import or catabolism in macrophages restricts intracellular growth of Mycobacterium tuberculosis.

Nelson V Simwela, Eleni Jaecklein, Christopher M Sassetti, David G Russell.

Mycobacterium tuberculosis ( Mtb ) infection of macrophages reprograms cellular metabolism to promote lipid retention. While it is clearly known that intracellular Mtb utilize host derived fatty acids and cholesterol to fuel the majority of its metabolic demands, the role of macrophage lipid catabolism on the bacteria's ability to access the intracellular lipid pool remains undefined. We utilized a CRISPR genetic knockdown approach to assess the impact of sequential steps in fatty acid metabolism on the growth of intracellular Mtb . Our analyzes demonstrate that knockdown of lipid import, sequestration and metabolism genes collectively impair the intracellular growth of Mtb in macrophages. We further demonstrate that modulating fatty acid homeostasis in macrophages impairs Mtb replication through diverse pathways like enhancing production of pro-inflammatory cytokines, autophagy, restricting the bacteria access to nutrients and increasing oxidative stress. We also show that impaired macrophage lipid droplet biogenesis is restrictive to intracellular Mtb replication, but increased induction of the same by blockade of downstream fatty acid oxidation fails to rescue Mtb growth. Our work expands our understanding of how host fatty acid homeostasis impacts Mtb growth in the macrophage.Significance: Mycobacterium tuberculosis ( Mtb ) primarily infects macrophages in the lungs. In infected macrophages, Mtb uses host lipids as key carbon sources to maintain infection and survive. In this work, we used a CRISPR-Cas9 gene knockout system in murine macrophages to examine the role of host fatty acid metabolism on the intracellular growth of Mtb . Our work shows that macrophages which cannot either import, store or catabolize fatty acids restrict Mtb growth by both common and divergent anti-microbial mechanisms, including increased glycolysis, increased production of reactive oxygen species, production of pro-inflammatory cytokines, enhanced autophagy and nutrient limitation. Our findings demonstrate that manipulating lipid metabolism in macrophages controls Mtb through multiple other mechanisms, beyond limiting the bacteria's access to nutrients.

DOI: https://doi.org/10.1101/2024.07.22.604660
Cell Rep. 2024 Aug 01. pii: S2211-1247(24)00899-4. [Epub ahead of print]43(8): 114570

Endogenously produced itaconate negatively regulates innate-driven cytokine production and drives global ubiquitination in human macrophages.

Luke A Bourner, Linda A Chung, Haiyan Long, Anne F McGettrick, Junpeng Xiao, Kenneth Roth, Jade D Bailey, Marie Strickland, Bo Tan, Jason Cunningham, Barry Lutzke, James McGee, Francella J Otero, David C Gemperline, Lin Zhang, Ying C Wang, Michael J Chalmers, Chiao-Wen Yang, Jesus A Gutierrez, Luke A J O'Neill, Frank C Dorsey.

  A wide variety of electrophilic derivatives of itaconate, the Kreb's cycle-derived metabolite, are immunomodulatory, yet these derivatives have overlapping and sometimes contradictory activities. Therefore, we generated a genetic system to interrogate the immunomodulatory functions of endogenously produced itaconate in human macrophages. Endogenous itaconate is driven by multiple innate signals restraining inflammatory cytokine production. Endogenous itaconate directly targets cysteine 13 in IRAK4 (disrupting IRAK4 autophosphorylation and activation), drives the degradation of nuclear factor κB, and modulates global ubiquitination patterns. As a result, cells unable to make itaconate overproduce inflammatory cytokines such as tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1β in response to these innate activators. In contrast, the production of interferon (IFN)β, downstream of LPS, requires the production of itaconate. These data demonstrate that itaconate is a critical arbiter of inflammatory cytokine production downstream of multiple innate signaling pathways, laying the groundwork for the development of itaconate mimetics for the treatment of autoimmunity.

Keywords:  ACOD1; CP: Immunology; IRAK4; IRG1; MYC; immunometabolism; itaconate; macrophage

DOI:  https://doi.org/10.1016/j.celrep.2024.114570
Autoimmun Rev. 2024 Jul 29. pii: S1568-9972(24)00074-0. [Epub ahead of print] 103583

Remodeling of T-cell mitochondrial metabolism to treat autoimmune diseases.

Liyan Lin, Ruyu Ren, Qiao Xiong, Chunfu Zheng, Bin Yang, Huiqing Wang.

  T cells are key drivers of the pathogenesis of autoimmune diseases by producing cytokines, stimulating the generation of autoantibodies, and mediating tissue and cell damage. Distinct mitochondrial metabolic pathways govern the direction of T-cell differentiation and function and rely on specific nutrients and metabolic enzymes. Metabolic substrate uptake and mitochondrial metabolism form the foundational elements for T-cell activation, proliferation, differentiation, and effector function, contributing to the dynamic interplay between immunological signals and mitochondrial metabolism in coordinating adaptive immunity. Perturbations in substrate availability and enzyme activity may impair T-cell immunosuppressive function, fostering autoreactive responses and disrupting immune homeostasis, ultimately contributing to autoimmune disease pathogenesis. A growing body of studies has explored how metabolic processes regulate the function of diverse T-cell subsets in autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), autoimmune hepatitis (AIH), inflammatory bowel disease (IBD), and psoriasis. This review describes the coordination of T-cell biology by mitochondrial metabolism, including the electron transport chain (ETC), oxidative phosphorylation, amino acid metabolism, fatty acid metabolism, and one‑carbon metabolism. This study elucidated the intricate crosstalk between mitochondrial metabolic programs, signal transduction pathways, and transcription factors. This review summarizes potential therapeutic targets for T-cell mitochondrial metabolism and signaling in autoimmune diseases, providing insights for future studies.

Keywords:  Autoimmune diseases; Fatty acid metabolism; Mitochondrial metabolism; OXPHOS; Regulatory T cells; T helper cells; Treatment

DOI:  https://doi.org/10.1016/j.autrev.2024.103583
Nat Commun. 2024 Jul 29. 15(1): 6390

Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice.

Mouna Chajadine, Ludivine Laurans, Tobias Radecke, Nirmala Mouttoulingam, Rida Al-Rifai, Emilie Bacquer, Clara Delaroque, Héloïse Rytter, Marius Bredon, Camille Knosp, José Vilar, Coralie Fontaine, Nadine Suffee, Marie Vandestienne, Bruno Esposito, Julien Dairou, Jean Marie Launay, Jacques Callebert, Alain Tedgui, Hafid Ait-Oufella, Harry Sokol, Benoit Chassaing, Soraya Taleb.

Tryptophan (Trp) is an essential amino acid, whose metabolism is a key gatekeeper of intestinal homeostasis. Yet, its systemic effects, particularly on atherosclerosis, remain unknown. Here we show that high-fat diet (HFD) increases the activity of intestinal indoleamine 2, 3-dioxygenase 1 (IDO), which shifts Trp metabolism from the production of microbiota-derived indole metabolites towards kynurenine production. Under HFD, the specific deletion of IDO in intestinal epithelial cells leads to intestinal inflammation, impaired intestinal barrier, augmented lesional T lymphocytes and atherosclerosis. This is associated with an increase in serotonin production and a decrease in indole metabolites, thus hijacking Trp for the serotonin pathway. Inhibition of intestinal serotonin production or supplementation with indole derivatives alleviates plaque inflammation and atherosclerosis. In summary, we uncover a pivotal role of intestinal IDO in the fine-tuning of Trp metabolism with systemic effects on atherosclerosis, paving the way for new therapeutic strategies to relieve gut-associated inflammatory diseases.

DOI: https://doi.org/10.1038/s41467-024-50807-x
Clin Transl Med. 2024 Aug;14(8): e1785

CPT1A-IL-10-mediated macrophage metabolic and phenotypic alterations ameliorate acute lung injury.

Muyun Wang, Di Wu, Ximing Liao, Haiyang Hu, Jing Gao, Linlin Meng, Feilong Wang, Wujian Xu, Shaoyong Gao, Jing Hua, Yuanyuan Wang, Qiang Li, Kun Wang, Wei Gao.

  BACKGROUND: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common acute respiratory failure due to diffuse pulmonary inflammation and oedema. Elaborate regulation of macrophage activation is essential for managing this inflammatory process and maintaining tissue homeostasis. In the past decades, metabolic reprogramming of macrophages has emerged as a predominant role in modulating their biology and function. Here, we observed reduced expression of carnitine palmitoyltransferase 1A (CPT1A), a key rate-limiting enzyme of fatty acid oxidation (FAO), in macrophages of lipopolysaccharide (LPS)-induced ALI mouse model. We assume that CPT1A and its regulated FAO is involved in the regulation of macrophage polarization, which could be positive regulated by interleukin-10 (IL-10).METHODS: After nasal inhalation rIL-10 and/or LPS, wild type (WT), IL-10-/-, Cre-CPT1Afl/fl and Cre+CPT1Afl/fl mice were sacrificed to harvest bronchoalveolar lavage fluid, blood serum and lungs to examine cell infiltration, cytokine production, lung injury severity and IHC. Bone marrow-derived macrophages (BMDMs) were extracted from mice and stimulated by exogenous rIL-10 and/or LPS. The qRT-PCR, Seahorse XFe96 and FAO metabolite related kits were used to test the glycolysis and FAO level in BMDMs. Immunoblotting assay, confocal microscopy and fluorescence microplate were used to test macrophage polarization as well as mitochondrial structure and function damage.
RESULTS: In in vivo experiments, we found that mice lacking CPT1A or IL-10 produced an aggravate inflammatory response to LPS stimulation. However, the addition of rIL-10 could alleviate the pulmonary inflammation in mice effectively. IHC results showed that IL-10 expression in lung macrophage decreased dramatically in Cre+CPT1Afl/fl mice. The in vitro experiments showed Cre+CPT1Afl/fl and IL-10-/- BMDMs became more "glycolytic", but less "FAO" when subjected to external attacks. However, the supplementation of rIL-10 into macrophages showed reverse effect. CPT1A and IL-10 can drive the polarization of BMDM from M1 phenotype to M2 phenotype, and CPT1A-IL-10 axis is also involved in the process of maintaining mitochondrial homeostasis.
CONCLUSIONS: CPT1A modulated metabolic reprogramming and polarisation of macrophage under LPS stimulation. The protective effects of CPT1A may be partly attributed to the induction of IL-10/IL-10 receptor expression.

Keywords:  acute lung injury; carnitine palmitoyltransferase 1A; fatty acid oxidation; interleukin‐10; macrophage

DOI:  https://doi.org/10.1002/ctm2.1785
JHEP Rep. 2024 Aug;6(8): 101101

Bile acids attenuate hepatic inflammation during ischemia/reperfusion injury.

Kunpeng Huang, Changyan Wang, Bosheng Mei, Jinglei Li, Tianxing Ren, Hanjing Zhan, Yunwei Zhang, Bowen Zhang, Xinyu Lv, Qi Zhang, Yong Guan, Xiaofei Zhang, Guoliang Wang, Wenming Pan, Peng Xu, Hui Wang, Jinxiang Zhang.

  Background & Aims: Persistent cholestasis has been associated with poor prognosis after orthotopic liver transplantation. In this study, we aimed to investigate how the accumulation of tauro-beta-muricholic acid (TβMCA), resulting from the reprogramming of bile acid (BA) metabolism during liver ischemia/reperfusion (IR) stress, attenuates liver inflammation.Methods: Ingenuity Pathway Analysis was performed using transcriptome data from a murine hepatic IR model. Three different models of hepatic IR (liver warm IR, bile duct separation-IR, common bile duct ligation-IR) were employed. We generated adeno-associated virus-transfected mice and CD11b-DTR mice to assess the role of BAs in regulating the myeloid S1PR2-GSDMD axis. Hepatic BA levels were analyzed using targeted metabolomics. Finally, the correlation between the reprogramming of BA metabolism and hepatic S1PR2 levels was validated through RNA-seq of human liver transplant biopsies.
Results: We found that BA metabolism underwent reprogramming in murine hepatocytes under IR stress, leading to increased synthesis of TβMCA, catalyzed by the enzyme CYP2C70. The levels of hepatic TβMCA were negatively correlated with the severity of hepatic inflammation, as indicated by the serum IL-1β levels. Inhibition of hepatic CYP2C70 resulted in reduced TβMCA production, which subsequently increased serum IL-1β levels and exacerbated IR injury. Moreover, our findings suggested that TβMCA could inhibit canonical inflammasome activation in macrophages and attenuate inflammatory responses in a myeloid-specific S1PR2-GSDMD-dependent manner. Additionally, Gly-βMCA, a derivative of TβMCA, could effectively attenuate inflammatory injury in vivo and inhibit human macrophage pyroptosis in vitro.
Conclusions: IR stress orchestrates hepatic BA metabolism to generate TβMCA, which attenuates hepatic inflammatory injury by inhibiting the myeloid S1PR2-GSDMD axis. Bile acids have immunomodulatory functions in liver reperfusion injury that may guide therapeutic strategies.
Impact and implications: Our research reveals that liver ischemia-reperfusion stress triggers reprogramming of bile acid metabolism. This functions as an adaptive mechanism to mitigate inflammatory injury by regulating the S1PR2-GSDMD axis, thereby controlling the release of IL-1β from macrophages. Our results highlight the crucial role of bile acids in regulating hepatocyte-immune cell crosstalk, which demonstrates an immunomodulatory function in liver reperfusion injury that may guide therapeutic strategies targeting bile acids and their receptors.

Keywords:  CYP2C70; GSDMD; Liver transplantation; Macrophages; Pyroptosis; S1PR2

DOI:  https://doi.org/10.1016/j.jhepr.2024.101101
FASEB J. 2024 Aug 15. 38(15): e23854

Hypoxia activates macrophage-NLRP3 inflammasome promoting atherosclerosis via PFKFB3-driven glycolysis.

Xuan Wang, Xiangbin Liu, Wanzhou Wu, Longshen Liao, Ming Zhou, Xiaobo Wang, Zeming Tan, Guogang Zhang, Yongping Bai, Xiang Li, Min Zhao.

  The onset and progression of atherosclerosis are closely linked to the involvement of macrophages. While the contribution of NLRP3 inflammasome activation to the creation of a local highly inflammatory microenvironment is well recognized, the precise triggers remain unclear. In this study, we aimed to investigate the regulatory mechanism of NLRP3 inflammasome activation in response to hypoxia-induced glycolysis involving PFKFB3 in the development of atherosclerosis. To develop an atherosclerosis model, we selected ApoE knockout mice treated with a high-fat western diet. We then quantified the expression of HIF-1α, PFKFB3, and NLRP3. In addition, we administered the PFKFB3 inhibitor PFK158 during atherosclerosis modeling. The glycolytic activity was subsequently determined through 18F-FDG micro-PET/CT, ex vivo glucose uptake, and ECAR analysis. Furthermore, we employed lipopolysaccharide (LPS) and TNF-α to induce the differentiation of bone marrow-derived macrophages (BMDMs) into M1-like phenotypes under both hypoxic and normoxic conditions. Our histological analyses revealed the accumulation of PFKFB3 in human atherosclerotic plaques, demonstrating colocalization with NLRP3 expression and macrophages. Treatment with PFK158 reduced glycolytic activity and NLRP3 inflammasome activation, thereby mitigating the occurrence of atherosclerosis. Mechanistically, hypoxia promoted glycolytic reprogramming and NLRP3 inflammasome activation in BMDMs. Subsequent blocking of either HIF-1α or PFKFB3 downregulated the NLRP3/Caspase-1/IL-1β pathway in hypoxic BMDMs. Our study demonstrated that the HIF-1α/PFKFB3/NLRP3 axis serves as a crucial mechanism for macrophage inflammation activation in the emergence of atherosclerosis. The therapeutic potential of PFKFB3 inhibition may represent a promising strategy for atheroprotection.

Keywords:  NLRP3; PFKFB3; atherosclerosis; hypoxia; macrophage

DOI:  https://doi.org/10.1096/fj.202400283R
Respir Res. 2024 Jul 30. 25(1): 291

Glycolytic enzyme PGK1 promotes M1 macrophage polarization and induces pyroptosis of acute lung injury via regulation of NLRP3.

Guiyin Zhu, Haiyang Yu, Tian Peng, Kun Yang, Xue Xu, Wen Gu.

  Acute lung injury (ALI) is characterized by an unregulated inflammatory reaction, often leading to severe morbidity and ultimately death. Excessive inflammation caused by M1 macrophage polarization and pyroptosis has been revealed to have a critical role in ALI. Recent study suggests that glycolytic reprogramming is important in the regulation of macrophage polarization and pyroptosis. However, the particular processes underlying ALI have yet to be identified. In this study, we established a Lipopolysaccharide(LPS)-induced ALI model and demonstrated that blocking glycolysis by using 2-Deoxy-D-glucose(2-DG) significantly downregulated the expression of M1 macrophage markers and pyroptosis-related genes, which was consistent with the in vitro results. Furthermore, our research has revealed that Phosphoglycerate Kinase 1(PGK1), an essential enzyme in the glycolysis pathway, interacts with NOD-, LRR- and pyrin domain-containing protein 3(NLRP3). We discovered that LPS stimulation improves the combination of PGK1 and NLRP3 both in vivo and in vitro. Interestingly, the absence of PGK1 reduces the phosphorylation level of NLRP3. Based on in vitro studies with mice bone marrow-derived macrophages (BMDMs), we further confirmed that siPGK1 plays a protective role by inhibiting macrophage pyroptosis and M1 macrophage polarization. The PGK1 inhibitor NG52 suppresses the occurrence of excessive inflammation in ALI. In general, it is plausible to consider a therapeutic strategy that focuses on modulating the relationship between PGK1 and NLRP3 as a means to mitigate the activation of inflammatory macrophages in ALI.

Keywords:  Acute lung injury; Glycolytic reprogramming; Macrophage polarization; Pyroptosis

DOI:  https://doi.org/10.1186/s12931-024-02926-8
J Immunol. 2024 Aug 02. pii: ji2300758. [Epub ahead of print]

Mitochondrial DNA Programs Lactylation of cGAS to Induce IFN Responses in Patients with Systemic Lupus Erythematosus.

Juan Zhang, Huiyan Ji, Mengdi Liu, Ming Zheng, Zhenke Wen, Haili Shen.

Mitochondrial DNA (mtDNA) is frequently released from mitochondria, activating cGAS-STING signaling and inducing type I IFNs (IFN-Is) in systemic lupus erythematosus (SLE). Meanwhile, whether and how the glycolytic pathway was involved in such IFN-I responses in human SLE remain unclear. In this study, we found that monocytes from SLE patients exerted robust IFN-I generation and elevated level of cytosolic mtDNA. Transfection of mtDNA into THP-1 macrophages was efficient in inducing IFN-I responses, together with the strong glycolytic pathway that promoted lactate production, mimicking the SLE phenotype. Blockade of lactate generation abrogated such IFN-I responses and, vice versa, exogenous lactate enhanced the IFN-I generation. Mechanistically, lactate promoted the lactylation of cGAS, which inhibited its binding to E3 ubiquitination ligase MARCHF5, blocking cGAS degradation and leading to strong IFN-I responses. In accordance, targeting lactate generation alleviated disease development in humanized SLE chimeras. Collectively, cytosolic mtDNA drives metabolic adaption toward the glycolytic pathway, promoting lactylation of cGAS for licensing IFN-I responses in human SLE and thereby assigning the glycolytic pathway as a promising therapeutic target for SLE.

DOI: https://doi.org/10.4049/jimmunol.2300758
Front Immunol. 2024 ;15 1414594

Hepatic macrophage niche: a bridge between HBV-mediated metabolic changes with intrahepatic inflammation.

Jun Wang, Hongzhou Lu, Qian Li.

  Hepatitis B Virus (HBV) is a stealthy and insidious pathogen capable of inducing chronic necro-inflammatory liver disease and hepatocellular carcinoma (HCC), resulting in over one million deaths worldwide per year. The traditional understanding of Chronic Hepatitis B (CHB) progression has focused on the complex interplay among ongoing virus replication, aberrant immune responses, and liver pathogenesis. However, the dynamic progression and crucial factors involved in the transition from HBV infection to immune activation and intrahepatic inflammation remain elusive. Recent insights have illuminated HBV's exploitation of the sodium taurocholate co-transporting polypeptide (NTCP) and manipulation of the cholesterol transport system shared between macrophages and hepatocytes for viral entry. These discoveries deepen our understanding of HBV as a virus that hijacks hepatocyte metabolism. Moreover, hepatic niche macrophages exhibit significant phenotypic and functional diversity, zonal characteristics, and play essential roles, either in maintaining liver homeostasis or contributing to the pathogenesis of chronic liver diseases. Therefore, we underscore recent revelations concerning the importance of hepatic niche macrophages in the context of viral hepatitis. This review particularly emphasizes the significant role of HBV-induced metabolic changes in hepatic macrophages as a key factor in the transition from viral infection to immune activation, ultimately culminating in liver inflammation. These metabolic alterations in hepatic macrophages offer promising targets for therapeutic interventions and serve as valuable early warning indicators, shedding light on the disease progression.

Keywords:  HBV; hepatic macrophage niches; lipid metabolism (fatty acids); liver inflammation; metabolism

DOI:  https://doi.org/10.3389/fimmu.2024.1414594
Transpl Int. 2024 ;37 13029

Glycolysis Changes in Alloreactive Memory B Cells in Highly Sensitized Kidney Transplant Recipients Undergonig Desensitization Therapy.

Johan Noble, Lara Cabezas, Aurelie Truffot, Lucile Dumolard, Thomas Jouve, Paolo Malvezzi, Lionel Rostaing, Céline Dard, Philippe Saas, Paolo Cravedi, Zuzana Macek-Jilkova.

  Despite the growing use of desensitization strategies, hyperimmune patients remain at high risk of antibody-mediated rejection suggesting that, even when donor-specific antibodies (DSA) are effectively depleted, anti-donor specific B cells persist. We included 10 highly sensitized recipients that underwent desensitization with plasmapheresis and B cell depletion prior to kidney transplantation. We quantified changes in DSA (luminex), total B-cell subsets (flow cytometry), anti-donor HLA B cells (fluorospot), and single-cell metabolism in serially collected samples before desensitization, at the time of transplant, and at 6 and 12 months thereafter. Desensitization was associated with a decrease in DSA and total memory B cell and naive B cell percentage, while plasma cells and memory anti-donor HLA circulating B cells persisted up to 12 months after transplant. At 12-month post-transplantation, memory B cells increased their glycolytic capacity, while proliferative KI67+ plasma cells modified their metabolism by increasing fatty acid and amino acid oxidation capacity and decreasing their glucose dependence. Despite effective DSA depletion, anti-donor B cells persist in kidney transplant recipients. Due to the reliance of these cells on glycolysis, glycolysis-targeting therapies might represent a valuable treatment strategy.

Keywords:  desensitization; donor-specific antibody; glycolysis; kidney transplantation; memory B cells; metabolism

DOI:  https://doi.org/10.3389/ti.2024.13029
Nat Commun. 2024 Jul 27. 15(1): 6340

Adenosine triggers early astrocyte reactivity that provokes microglial responses and drives the pathogenesis of sepsis-associated encephalopathy in mice.

Qilin Guo, Davide Gobbo, Na Zhao, Hong Zhang, Nana-Oye Awuku, Qing Liu, Li-Pao Fang, Tanja M Gampfer, Markus R Meyer, Renping Zhao, Xianshu Bai, Shan Bian, Anja Scheller, Frank Kirchhoff, Wenhui Huang.

Molecular pathways mediating systemic inflammation entering the brain parenchyma to induce sepsis-associated encephalopathy (SAE) remain elusive. Here, we report that in mice during the first 6 hours of peripheral lipopolysaccharide (LPS)-evoked systemic inflammation (6 hpi), the plasma level of adenosine quickly increased and enhanced the tone of central extracellular adenosine which then provoked neuroinflammation by triggering early astrocyte reactivity. Specific ablation of astrocytic Gi protein-coupled A1 adenosine receptors (A1ARs) prevented this early reactivity and reduced the levels of inflammatory factors (e.g., CCL2, CCL5, and CXCL1) in astrocytes, thereby alleviating microglial reaction, ameliorating blood-brain barrier disruption, peripheral immune cell infiltration, neuronal dysfunction, and depression-like behaviour in the mice. Chemogenetic stimulation of Gi signaling in A1AR-deficent astrocytes at 2 and 4 hpi of LPS injection could restore neuroinflammation and depression-like behaviour, highlighting astrocytes rather than microglia as early drivers of neuroinflammation. Our results identify early astrocyte reactivity towards peripheral and central levels of adenosine as an important pathway driving SAE and highlight the potential of targeting A1ARs for therapeutic intervention.

DOI: https://doi.org/10.1038/s41467-024-50466-y