bims-imicid 2024-09-15 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–09–15
twenty-six papers selected by
Dylan Ryan, University of Cambridge

Endothelial metabolic control of insulin sensitivity through resident macrophages.
The bacterial quorum sensing signal 2'-aminoacetophenone rewires immune cell bioenergetics through the Ppargc1a/Esrra axis to mediate tolerance to infection.
CPT2-mediated Fatty Acid Oxidation Is Dispensable for Humoral Immunity.
Gasdermin D-mediated metabolic crosstalk promotes tissue repair.
Glycolytic metabolism: Food for immune cells, fuel for depression?
Efferocytosis drives a tryptophan metabolism pathway in macrophages to promote tissue resolution.
Controlling functional homeostasis of ileal resident macrophages by vitamin B12 during steady state and Salmonella infection in mice.
RBM25 is required to restrain inflammation via ACLY RNA splicing-dependent metabolism rewiring.
Differential roles for the oxygen sensing enzymes PHD1 and PHD3 in the regulation of neutrophil metabolism and function.
The Kynurenine Pathway Regulated by Intestinal Innate Lymphoid Cells Mediates Postoperative Cognitive Dysfunction.
A pinch of salt boosts T cell function.
Crosstalk between Dysfunctional Mitochondria and Proinflammatory Responses during Viral Infections.
Single-cell transcriptomics reveals subset-specific metabolic profiles underpinning the bronchial epithelial response to flagellin.
Dissecting the metabolic signaling pathways by which microbial molecules drive the differentiation of regulatory B cells.
HIV-TAT dysregulates microglial lipid metabolism through SREBP2/miR-124 axis: Implication of lipid droplet accumulation microglia in NeuroHIV.
Enhanced tumor response to adoptive T cell therapy with PHD2/3-deficient CD8 T cells.
Inherent metabolic preferences differentially regulate the sensitivity of Th1 and Th2 cells to ribosome-inhibiting antibiotics.
IRF5 mediates adaptive immunity via altered glutamine metabolism, mTORC1 signaling and post-transcriptional regulation following T cell receptor activation.
Metabolic Pathways Affected in Patients Undergoing Hemodialysis and Their Relationship with Inflammation.
Enhanced mitochondrial function in B cells from elderly type-2 diabetes mellitus patients supports intrinsic inflammation.
Itaconate to treat acute lung injury: recent advances and insights from preclinical models.
Time-resolved multi-omics reveals diverse metabolic strategies of Salmonella during diet-induced inflammation.
IDH2 regulates macrophage polarization and tumorigenesis by modulating mitochondrial metabolism in macrophages.
A mouse protozoan boosts antigen-specific mucosal IgA responses in a specific lipid metabolism- and signaling-dependent manner.
Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells.
Branched-chain amino acids supplementation induces insulin resistance and pro-inflammatory macrophage polarization via INFGR1/JAK1/STAT1 signal pathway.

Cell Metab. 2024 Sep 08. pii: S1550-4131(24)00335-8. [Epub ahead of print]

Endothelial metabolic control of insulin sensitivity through resident macrophages.

Jing Zhang, Kim Anker Sjøberg, Songlin Gong, Tongtong Wang, Fengqi Li, Andrew Kuo, Stephan Durot, Adam Majcher, Raphaela Ardicoglu, Thibaut Desgeorges, Charlotte Greta Mann, Ines Soro Arnáiz, Gillian Fitzgerald, Paola Gilardoni, E Dale Abel, Shigeyuki Kon, Danyvid Olivares-Villagómez, Nicola Zamboni, Christian Wolfrum, Thorsten Hornemann, Raphael Morscher, Nathalie Tisch, Bart Ghesquière, Manfred Kopf, Erik A Richter, Katrien De Bock.

  Endothelial cells (ECs) not only form passive blood conduits but actively contribute to nutrient transport and organ homeostasis. The role of ECs in glucose homeostasis is, however, poorly understood. Here, we show that, in skeletal muscle, endothelial glucose transporter 1 (Glut1/Slc2a1) controls glucose uptake via vascular metabolic control of muscle-resident macrophages without affecting transendothelial glucose transport. Lowering endothelial Glut1 via genetic depletion (Glut1ΔEC) or upon a short-term high-fat diet increased angiocrine osteopontin (OPN/Spp1) secretion. This promoted resident muscle macrophage activation and proliferation, which impaired muscle insulin sensitivity. Consequently, co-deleting Spp1 from ECs prevented macrophage accumulation and improved insulin sensitivity in Glut1ΔEC mice. Mechanistically, Glut1-dependent endothelial glucose metabolic rewiring increased OPN in a serine metabolism-dependent fashion. Our data illustrate how the glycolytic endothelium creates a microenvironment that controls resident muscle macrophage phenotype and function and directly links resident muscle macrophages to the maintenance of muscle glucose homeostasis.

Keywords:  GLUT1; endothelial cells; endothelial metabolism; inflammation; insulin sensitivity; osteopontin; resident macrophages; serine; skeletal muscle; vasculature

DOI:  https://doi.org/10.1016/j.cmet.2024.08.008
Elife. 2024 Sep 13. pii: RP97568. [Epub ahead of print]13

The bacterial quorum sensing signal 2'-aminoacetophenone rewires immune cell bioenergetics through the Ppargc1a/Esrra axis to mediate tolerance to infection.

Arijit Chakraborty, Arunava Bandyopadhaya, Vijay K Singh, Filip Kovacic, Sujin Cha, William M Oldham, A Aria Tzika, Laurence G Rahme.

  How bacterial pathogens exploit host metabolism to promote immune tolerance and persist in infected hosts remains elusive. To achieve this, we show that Pseudomonas aeruginosa (PA), a recalcitrant pathogen, utilizes the quorum sensing (QS) signal 2'-aminoacetophenone (2-AA). Here, we unveil how 2-AA-driven immune tolerization causes distinct metabolic perturbations in murine macrophages' mitochondrial respiration and bioenergetics. We present evidence indicating that these effects stem from decreased pyruvate transport into mitochondria. This reduction is attributed to decreased expression of the mitochondrial pyruvate carrier (Mpc1), which is mediated by diminished expression and nuclear presence of its transcriptional regulator, estrogen-related nuclear receptor alpha (Esrra). Consequently, Esrra exhibits weakened binding to the Mpc1 promoter. This outcome arises from the impaired interaction between Esrra and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a). Ultimately, this cascade results in diminished pyruvate influx into mitochondria and, consequently reduced ATP production in tolerized murine and human macrophages. Exogenously added ATP in infected macrophages restores the transcript levels of Mpc1 and Esrra and enhances cytokine production and intracellular bacterial clearance. Consistent with the in vitro findings, murine infection studies corroborate the 2-AA-mediated long-lasting decrease in ATP and acetyl-CoA and its association with PA persistence, further supporting this QS signaling molecule as the culprit of the host bioenergetic alterations and PA persistence. These findings unveil 2-AA as a modulator of cellular immunometabolism and reveal an unprecedented mechanism of host tolerance to infection involving the Ppargc1a/Esrra axis in its influence on Mpc1/OXPHOS-dependent energy production and PA clearance. These paradigmatic findings pave the way for developing treatments to bolster host resilience to pathogen-induced damage. Given that QS is a common characteristic of prokaryotes, it is likely that 2-AA-like molecules with similar functions may be present in other pathogens.

Keywords:  2'-aminoacetophenone; Esrra; MvfR; PqsR; Pseudomonas aeruginosa; immunology; inflammation; mouse; pseudomonas; quorum sensing; tolerance to infection

DOI:  https://doi.org/10.7554/eLife.97568
J Immunol. 2024 Sep 11. pii: ji2400285. [Epub ahead of print]

CPT2-mediated Fatty Acid Oxidation Is Dispensable for Humoral Immunity.

Meilu Li, Xian Zhou, Yanfeng Li, Xingxing Zhu, Yuzhen Li, Taro Hitosugi, Hu Zeng.

B cell activation is accompanied by dynamic metabolic reprogramming, supported by a multitude of nutrients that include glucose, amino acids, and fatty acids. Although several studies have indicated that fatty acid mitochondrial oxidation is critical for immune cell functions, contradictory findings have been reported. Carnitine palmitoyltransferase II (CPT2) is a critical enzyme for long-chain fatty acid oxidation in mitochondria. In this study, we test the requirement of CPT2 for humoral immunity using a mouse model with a lymphocyte-specific deletion of CPT2. Stable [13C] isotope tracing reveals highly reduced fatty acid-derived citrate production in CPT2-deficient B cells. Yet, CPT2 deficiency has no significant impact on B cell development, B cell activation, germinal center formation, and Ab production upon either thymus-dependent or -independent Ag challenges. Together, our findings indicate that CPT2-mediated fatty acid oxidation is dispensable for humoral immunity, highlighting the metabolic flexibility of lymphocytes.

DOI: https://doi.org/10.4049/jimmunol.2400285
Nature. 2024 Sep 11.

Gasdermin D-mediated metabolic crosstalk promotes tissue repair.

Zhexu Chi, Sheng Chen, Dehang Yang, Wenyu Cui, Yang Lu, Zhen Wang, Mobai Li, Weiwei Yu, Jian Zhang, Yu Jiang, Ruya Sun, Qianzhou Yu, Tianyi Hu, Xiaoyang Lu, Qiqi Deng, Yidong Yang, Tianming Zhao, Mengfei Chang, Yuying Li, Xue Zhang, Min Shang, Qian Xiao, Kefeng Ding, Di Wang.

The establishment of an early pro-regenerative niche is crucial for tissue regeneration1,2. Gasdermin D (GSDMD)-dependent pyroptosis accounts for the release of inflammatory cytokines upon various insults3-5. However, little is known about its role in tissue regeneration followed by homeostatic maintenance. Here, we show that macrophage GSDMD deficiency delayed tissue recovery, with little impact on the local inflammatory milieu or the lytic pyroptosis process. Metabolite secretome profiling of hyperactivated macrophages unveiled the non-canonical metabolite-secreting function of GSDMD. And we further identified 11,12-epoxyeicosatrienoic acid (11,12-EET) as a bioactive pro-healing oxylipin, secreted from hyperactive macrophages in a GSDMD-dependent manner. Indeed, accumulation of 11,12-EET by direct supplementation or deletion of its hydrolytic enzyme Ephx2 accelerated muscle regeneration. We further demonstrated that the Ephx2 level accumulated within aged muscle. And consecutive 11,12-EET treatment rejuvenated aged muscle. Mechanistically, 11,12-EET amplifies FGF-FGFR signaling by modulating FGF liquid-liquid phase separation, hence boosting the activation and proliferation of muscle stem cells (MuSCs). These data depict a GSDMD-guided metabolite crosstalk between macrophages and MuSCs that governs the repair process, which offers new therapeutic insights for the regeneration of injured or aged tissues.

DOI: https://doi.org/10.1038/s41586-024-08022-7
Brain Behav Immun Health. 2024 Oct;40 100843

Glycolytic metabolism: Food for immune cells, fuel for depression?

Mandakh Bekhbat.

  Inflammation is one biological pathway thought to impact the brain to contribute to major depressive disorder (MDD) and is reliably associated with resistance to standard antidepressant treatments. While peripheral immune cells, particularly monocytes, have been associated with aspects of increased inflammation in MDD and symptom severity, significant gaps in knowledge exist regarding the mechanisms by which these cells are activated to contribute to behavioral symptoms in MDD. One concept that has gained recent appreciation is that metabolic rewiring to glycolysis in activated myeloid cells plays a crucial role in facilitating these cells' pro-inflammatory functions, which may underlie myeloid contribution to systemic inflammation and its effects on the brain. Given emerging evidence from translational studies of depression that peripheral monocytes exhibit signs of glycolytic activation, better understanding the immunometabolic phenotypes of monocytes which are known to be elevated in MDD with high inflammation is a critical step toward comprehending and treating the impact of inflammation on the brain. This narrative review examines the extant literature on glycolytic metabolism of circulating monocytes in depression and discusses the functional implications of immunometabolic shifts at both cellular and systemic levels. Additionally, it proposes potential therapeutic applications of existing immunomodulators that target glycolysis and related metabolic pathways in order to reverse the impact of elevated inflammation on the brain and depressive symptoms.

Keywords:  Depression; Glucose; Glycolysis; Immunometabolism; Inflammation; Monocyte

DOI:  https://doi.org/10.1016/j.bbih.2024.100843
Nat Metab. 2024 Sep 06.

Efferocytosis drives a tryptophan metabolism pathway in macrophages to promote tissue resolution.

Santosh R Sukka, Patrick B Ampomah, Lancia N F Darville, David Ngai, Xiaobo Wang, George Kuriakose, Yuling Xiao, Jinjun Shi, John M Koomen, Robert H McCusker, Ira Tabas.

Macrophage efferocytosis prevents apoptotic cell (AC) accumulation and triggers inflammation-resolution pathways. The mechanisms linking efferocytosis to resolution often involve changes in macrophage metabolism, but many gaps remain in our understanding of these processes. We now report that efferocytosis triggers an indoleamine 2,3-dioxygenase-1 (IDO1)-dependent tryptophan (Trp) metabolism pathway that promotes several key resolution processes, including the induction of pro-resolving proteins, such interleukin-10, and further enhancement of efferocytosis. The process begins with upregulation of Trp transport and metabolism, and it involves subsequent activation of the aryl hydrocarbon receptor (AhR) by the Trp metabolite kynurenine (Kyn). Through these mechanisms, macrophage IDO1 and AhR contribute to a proper resolution response in several different mouse models of efferocytosis-dependent tissue repair, notably during atherosclerosis regression induced by plasma low-density lipoprotein (LDL) lowering. These findings reveal an integrated metabolism programme in macrophages that links efferocytosis to resolution, with possible therapeutic implications for non-resolving chronic inflammatory diseases, notably atherosclerosis.

DOI: https://doi.org/10.1038/s42255-024-01115-7
Mucosal Immunol. 2024 Sep 08. pii: S1933-0219(24)00091-6. [Epub ahead of print]

Controlling functional homeostasis of ileal resident macrophages by vitamin B12 during steady state and Salmonella infection in mice.

Yong Ge, Mojgan Zadeh, Cheshta Sharma, Yang-Ding Lin, Alexey A Soshnev, Mansour Mohamadzadeh.

  Dietary micronutrients, particularly vitamin B12 (VB12), profoundly influence the physiological maintenance and function of intestinal cells. However, it is still unclear whether VB12 modulates the transcriptional and metabolic programming of ileal macrophages (iMacs), thereby contributing to intestinal homeostasis. Using multiomic approaches, we demonstrated that VB12 primarily supports the cell cycle activity and mitochondrial metabolism of iMacs, resulting in increased cell frequency compared to VB12 deficiency. VB12 also retained the ability to promote maintenance and metabolic regulation of iMacs during intestinal infection with Salmonella Typhimurium (STm). On the contrary, depletion of iMacs by inhibiting CSF1R signaling significantly increased host susceptibility to STm and prevented VB12-mediated pathogen reduction. These results thus suggest that regulation of VB12-dependent iMacs critically controls STm expansion, which may be of new relevance to advance our understanding of this vitamin and to strategically formulate sustainable therapeutic nutritional regimens that improve human gut health.

Keywords:  Ileal resident macrophages; Mitochondria; Salmonella infection; Vitamin B12

DOI:  https://doi.org/10.1016/j.mucimm.2024.08.011
Cell Mol Immunol. 2024 Sep 09.

RBM25 is required to restrain inflammation via ACLY RNA splicing-dependent metabolism rewiring.

Yunkai Zhang, Ying Gao, Yujia Wang, Yuyu Jiang, Yan Xiang, Xiaohui Wang, Zeting Wang, Yingying Ding, Huiying Chen, Bing Rui, Wanwan Huai, Boyu Cai, Xiaomeng Ren, Feng Ma, Sheng Xu, Zhenzhen Zhan, Xingguang Liu.

  Spliceosome dysfunction and aberrant RNA splicing underline unresolved inflammation and immunopathogenesis. Here, we revealed the misregulation of mRNA splicing via the spliceosome in the pathogenesis of rheumatoid arthritis (RA). Among them, decreased expression of RNA binding motif protein 25 (RBM25) was identified as a major pathogenic factor in RA patients and experimental arthritis mice through increased proinflammatory mediator production and increased hyperinflammation in macrophages. Multiomics analyses of macrophages from RBM25-deficient mice revealed that the transcriptional enhancement of proinflammatory genes (including Il1b, Il6, and Cxcl10) was coupled with histone 3 lysine 9 acetylation (H3K9ac) and H3K27ac modifications as well as hypoxia inducible factor-1α (HIF-1α) activity. Furthermore, RBM25 directly bound to and mediated the 14th exon skipping of ATP citrate lyase (Acly) pre-mRNA, resulting in two distinct Acly isoforms, Acly Long (Acly L) and Acly Short (Acly S). In proinflammatory macrophages, Acly L was subjected to protein lactylation on lysine 918/995, whereas Acly S did not, which influenced its affinity for metabolic substrates and subsequent metabolic activity. RBM25 deficiency overwhelmingly increased the expression of the Acly S isoform, enhancing glycolysis and acetyl-CoA production for epigenetic remodeling, macrophage overactivation and tissue inflammatory injury. Finally, macrophage-specific deletion of RBM25 led to inflammaging, including spontaneous arthritis in various joints of mice and inflammation in multiple organs, which could be relieved by pharmacological inhibition of Acly. Overall, targeting the RBM25-Acly splicing axis represents a potential strategy for modulating macrophage responses in autoimmune arthritis and aging-associated inflammation.

Keywords:  Acly; Histone acetylation; Inflammation; Metabolic reprogramming; RBM25; Splicing factor

DOI:  https://doi.org/10.1038/s41423-024-01212-3
Wellcome Open Res. 2023 ;8 569

Differential roles for the oxygen sensing enzymes PHD1 and PHD3 in the regulation of neutrophil metabolism and function.

Emily Watts, Joseph Willison, Simone Arienti, Pranvera Sadiku, Patricia Coelho, Manuel Sanchez-Garcia, Ailiang Zhang, Fiona Murphy, Rebecca Dickinson, Ananda Mirchandani, Tyler Morrison, Amy Lewis, Wesley Vermaelen, Bart Ghesquiere, Peter Carmeliet, Massimilliano Mazzone, Patrick Maxwell, Christopher Pugh, David Dockrell, Moira Whyte, Sarah Walmsley.

   Background: Neutrophils are essential in the early innate immune response to pathogens. Harnessing their antimicrobial powers, without driving excessive and damaging inflammatory responses, represents an attractive therapeutic possibility. The neutrophil population is increasingly recognised to be more diverse and malleable than was previously appreciated. Hypoxic signalling pathways are known to regulate important neutrophil behaviours and, as such, are potential therapeutic targets for regulating neutrophil antimicrobial and inflammatory responses.
Methods: We used a combination of in vivo and ex vivo models, utilising neutrophil and myeloid specific PHD1 or PHD3 deficient mouse lines to investigate the roles of oxygen sensing prolyl hydroxylase enzymes in the regulation of neutrophilic inflammation and immunity. Mass spectrometry and Seahorse metabolic flux assays were used to analyse the role of metabolic shifts in driving the downstream phenotypes.
Results: We found that PHD1 deficiency drives alterations in neutrophil metabolism and recruitment, in an oxygen dependent fashion. Despite this, PHD1 deficiency did not significantly alter ex vivo neutrophil phenotypes or in vivo outcomes in mouse models of inflammation. Conversely, PHD3 deficiency was found to enhance neutrophil antibacterial properties without excessive inflammatory responses. This was not linked to changes in the abundance of core metabolites but was associated with increased oxygen consumption and increased mitochondrial reactive oxygen species (mROS) production.
Conclusions: PHD3 deficiency drives a favourable neutrophil phenotype in infection and, as such, is an important potential therapeutic target.

Keywords:  Hypoxia; Inflammation; Neutrophil; PHD1; PHD3; Prolyl hydroxylase

DOI:  https://doi.org/10.12688/wellcomeopenres.19915.2
Mucosal Immunol. 2024 Sep 07. pii: S1933-0219(24)00095-3. [Epub ahead of print]

The Kynurenine Pathway Regulated by Intestinal Innate Lymphoid Cells Mediates Postoperative Cognitive Dysfunction.

Wan-Bing Dai, Xiao Zhang, Xu-Liang Jiang, Yi-Zhe Zhang, Ling-Ke Chen, Wei-Tian Tian, Xiao-Xin Zhou, Xiao-Yu Sun, Li-Li Huang, Xi-Yao Gu, Xue-Mei Chen, Xiao-Dan Wu, Jie Tian, Wei-Feng Yu, Lei Shen, Dian-San Su.

  Postoperative cognitive dysfunction (POCD) is a prevalent neurological complication that can impair learning and memory for days, months, or even years after anesthesia/surgery. POCD is strongly associated with an altered composition of the gut microbiota (dysbiosis), but the accompanying metabolic changes and their role in gut-brain communication and POCD pathogenesis remain unclear. Here, the present study reports that anesthesia/surgery in aged mice induces elevated intestinal indoleamine 2,3-dioxygenase (IDO) activity, which shiftes intestinal tryptophan (TRP) metabolism toward more IDO-catalyzed kynurenine (KYN) and less gut bacteria-catabolized indoleacetic acid (IAA). Both anesthesia/surgery and intraperitoneal KYN administration induce increased KYN levels that correlate with impaired spatial learning and memory, whereas dietary IAA supplementation attenuates the anesthesia/surgery-induced cognitive impairment. Mechanistically, anesthesia/surgery increases the proportion of interferon-γ (IFN-γ)-producing group 1 innate lymphoid cells (ILC1) in the small intestine lamina propria and elevates intestinal IDO expression and activity, as indicated by the higher ratio of KYN to TRP. The IDO inhibitor 1-MT and antibodies targeting IFN-γ or ILCs mitigate anesthesia/surgery-induced cognitive dysfunction, suggesting that intestinal ILC1 expansion and the ensuing IFN-γ-induced IDO upregulation may be the primary pathway mediating the shift to the KYN pathway in POCD. The ILC1-KYN pathway in the intestine could be a promising therapeutic target for POCD.

Keywords:  innate lymphoid cells; interferon-γ; kynurenine; postoperative cognitive dysfunction; tryptophan metabolism

DOI:  https://doi.org/10.1016/j.mucimm.2024.09.002
Nat Immunol. 2024 Sep 09.

A pinch of salt boosts T cell function.

Karina L Hajdu, Lorène Rousseau, Ping-Chih Ho.

DOI: https://doi.org/10.1038/s41590-024-01946-2
Int J Mol Sci. 2024 Aug 24. pii: 9206. [Epub ahead of print]25(17):

Crosstalk between Dysfunctional Mitochondria and Proinflammatory Responses during Viral Infections.

Zitao Sun, Yanjin Wang, Xin Jin, Su Li, Hua-Ji Qiu.

  Mitochondria play pivotal roles in sustaining various biological functions including energy metabolism, cellular signaling transduction, and innate immune responses. Viruses exploit cellular metabolic synthesis to facilitate viral replication, potentially disrupting mitochondrial functions and subsequently eliciting a cascade of proinflammatory responses in host cells. Additionally, the disruption of mitochondrial membranes is involved in immune regulation. During viral infections, mitochondria orchestrate innate immune responses through the generation of reactive oxygen species (ROS) and the release of mitochondrial DNA, which serves as an effective defense mechanism against virus invasion. The targeting of mitochondrial damage may represent a novel approach to antiviral intervention. This review summarizes the regulatory mechanism underlying proinflammatory response induced by mitochondrial damage during viral infections, providing new insights for antiviral strategies.

Keywords:  innate immunity; mitochondrial damage; mitochondrial dysfunction; proinflammatory responses

DOI:  https://doi.org/10.3390/ijms25179206
iScience. 2024 Sep 20. 27(9): 110662

Single-cell transcriptomics reveals subset-specific metabolic profiles underpinning the bronchial epithelial response to flagellin.

Ivan Ramirez-Moral, Alex R Schuurman, Christine C A van Linge, Joe M Butler, Xiao Yu, Karen de Haan, Sarah van Leeuwen, Alex F de Vos, Menno D de Jong, Felipe A Vieira Braga, Tom van der Poll.

  Airway epithelial cells represent the first line of defense against respiratory pathogens. Flagellin drives the motility of many mucosal pathogens and has been suggested as an immune enhancing adjunctive therapeutic in infections of the airways. This study leveraged single-cell RNA sequencing to determine cell-specific effects of flagellin in primary human bronchial epithelial cells growing in air-liquid interface. Seven cell clusters were identified, including ciliated cells, ionocytes, and several states of basal and secretory cells, of which only inflammatory basal cells and inflammatory secretory cells demonstrated a proportional increase in response to flagellin. Inflammatory secretory cells showed evidence of metabolic reprogramming toward aerobic glycolysis, while in inflammatory basal cells transcriptome profiles indicated enhanced oxidative phosphorylation. Inhibition of mTOR prevented the shift to glycolysis and reduced inflammatory gene transcription specifically in inflammatory secretory cells. These data demonstrate the functional heterogeneity of the human airway epithelium upon exposure to flagellin.

Keywords:  Biochemistry; Cellular physiology; Physiology; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.110662
Mucosal Immunol. 2024 Sep 10. pii: S1933-0219(24)00096-5. [Epub ahead of print]

Dissecting the metabolic signaling pathways by which microbial molecules drive the differentiation of regulatory B cells.

Maik Luu, Felix F Krause, Heide Monning, Anne Wempe, Hanna Leister, Lisa Mainieri, Sarah Staudt, Kai Ziegler-Martin, Kira Mangold, Nora Kappelhoff, Yoav D Shaul, Stephan Göttig, Carlos Plaza-Sirvent, Leon N Schulte, Isabelle Bekeredjian-Ding, Ingo Schmitz, Ulrich Steinhoff, Alexander Visekruna.

  The host-microbiome axis has been implicated in promoting anti-inflammatory immune responses. Yet, the underlying molecular mechanisms of commensal-mediated IL-10 production by regulatory B cells (Bregs) are not fully elucidated. Here, we demonstrate that bacterial CpG motifs trigger the signaling downstream of TLR9 promoting IκBNS-mediated expression of Blimp-1, a transcription regulator of IL-10. Surprisingly, this effect was counteracted by the NF-κB transcription factor c-Rel. A functional screen for intestinal bacterial species identified the commensal Clostridium sporogenes, secreting high amounts of short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs), as an amplifier of IL-10 production by promoting sustained mTOR signaling in B cells. Consequently, enhanced Breg functionality was achieved by combining CpG with the SCFA butyrate or the BCFA isovalerate thereby synergizing TLR- and mTOR-mediated pathways. Collectively, Bregs required two bacterial signals (butyrate and CpG) to elicit their full suppressive capacity and ameliorate T cell-mediated intestinal inflammation. Our study has dissected the molecular pathways induced by bacterial factors, which might contribute not only to better understanding of host-microbiome interactions, but also to exploration of new strategies for improvement of anti-inflammatory cellular therapy.

Keywords:  NF-kB; Regulatory B cells; colitis; microbial metabolites; microbiota

DOI:  https://doi.org/10.1016/j.mucimm.2024.09.003
Brain Behav Immun. 2024 Sep 09. pii: S0889-1591(24)00602-0. [Epub ahead of print]

HIV-TAT dysregulates microglial lipid metabolism through SREBP2/miR-124 axis: Implication of lipid droplet accumulation microglia in NeuroHIV.

Yan Cheng, Jaekeun Jung, Liyang Guo, Dorela D Shuboni-Mulligan, Jian-Fu Chen, Wenhui Hu, Ming-Lei Guo.

  Chronic HIV infection can dysregulate lipid/cholesterol metabolism in the peripheral system, contributing to the higher incidences of diabetes and atherosclerosis in HIV (+) individuals. Recently, accumulating evidence indicate that HIV proteins can also dysregulate lipid/cholesterol metabolism in the brain and such dysregulation could be linked with the pathogenesis of HIV-associated neurological disorders (HAND)/NeuroHIV. To further characterize the association between lipid/cholesterol metabolism and HAND, we employed HIV-inducible transactivator of transcription (iTAT) and control mice to compare their brain lipid profiles. Our results reveal that HIV-iTAT mice possess dysregulated lipid profiles and have increased numbers of lipid droplets (LDs) accumulation microglia (LDAM) in the brains. HIV protein TAT can upregulate LDs formation through enhancing the lipid/cholesterol synthesis in vitro. Mechanistically, HIV-TAT increases the expression of sterol regulatory element-binding protein 2 (SREBP2) through microRNA-124 downregulation. Cholesterol synthesis inhibition can block HIV-TAT-mediated NLRP3 inflammasome activation and microglial activation in vitro as well as mitigate aging-related behavioral impairment and memory deficiency in HIV-iTAT mice. Taken together, our results indicate an inherent role of lipid metabolism and LDAM in the pathogenesis of NeuroHIV (immunometabolism). These findings suggest that LDAM reversal through modulating lipid/cholesterol metabolism could be a novel therapeutic target for ameliorating NeuroHIV symptoms in chronic HIV (+) individuals.

Keywords:  Cholesterol; HIV-TAT; Microglia; NeuroHIV; SREBP2; miR-124

DOI:  https://doi.org/10.1016/j.bbi.2024.09.011
Nat Commun. 2024 Sep 06. 15(1): 7789

Enhanced tumor response to adoptive T cell therapy with PHD2/3-deficient CD8 T cells.

Tereza Dvorakova, Veronica Finisguerra, Matteo Formenti, Axelle Loriot, Loubna Boudhan, Jingjing Zhu, Benoit J Van den Eynde.

While adoptive cell therapy has shown success in hematological malignancies, its potential against solid tumors is hindered by an immunosuppressive tumor microenvironment (TME). In recent years, members of the hypoxia-inducible factor (HIF) family have gained recognition as important regulators of T-cell metabolism and function. The role of HIF signalling in activated CD8 T cell function in the context of adoptive cell transfer, however, has not been explored in full depth. Here we utilize CRISPR-Cas9 technology to delete prolyl hydroxylase domain-containing enzymes (PHD) 2 and 3, thereby stabilizing HIF-1 signalling, in CD8 T cells that have already undergone differentiation and activation, modelling the T cell phenotype utilized in clinical settings. We observe a significant boost in T-cell activation and effector functions following PHD2/3 deletion, which is dependent on HIF-1α, and is accompanied by an increased glycolytic flux. This improvement in CD8 T cell performance translates into an enhancement in tumor response to adoptive T cell therapy in mice, across various tumor models, even including those reported to be extremely resistant to immunotherapeutic interventions. These findings hold promise for advancing CD8 T-cell based therapies and overcoming the immune suppression barriers within challenging tumor microenvironments.

DOI: https://doi.org/10.1038/s41467-024-51782-z
Immunology. 2024 Sep 12.

Inherent metabolic preferences differentially regulate the sensitivity of Th1 and Th2 cells to ribosome-inhibiting antibiotics.

Neha Jawla, Raunak Kar, Veena S Patil, G Aneeshkumar Arimbasseri.

  Mitochondrial translation is essential to maintain mitochondrial function and energy production. Mutations in genes associated with mitochondrial translation cause several developmental disorders, and immune dysfunction is observed in many such patients. Besides genetic mutations, several antibiotics targeting bacterial ribosomes are well-established to inhibit mitochondrial translation. However, the effect of such antibiotics on different immune cells is not fully understood. Here, we addressed the differential effect of mitochondrial translation inhibition on different subsets of helper T cells (Th) of mice and humans. Inhibition of mitochondrial translation reduced the levels of mitochondrially encoded electron transport chain subunits without affecting their nuclear-encoded counterparts. As a result, mitochondrial oxygen consumption reduced dramatically, but mitochondrial mass was unaffected. Most importantly, we show that inhibition of mitochondrial translation induced apoptosis, specifically in Th2 cells. This increase in apoptosis was associated with higher expression of Bim and Puma, two activators of the intrinsic pathway of apoptosis. We propose that this difference in the sensitivity of Th1 and Th2 cells to mitochondrial translation inhibition reflects the intrinsic metabolic demands of these subtypes. Though Th1 and Th2 cells exhibit similar levels of oxidative phosphorylation, Th1 cells exhibit higher levels of aerobic glycolysis than Th2 cells. Moreover, Th1 cells are more sensitive to the inhibition of glycolysis, while higher concentrations of glycolysis inhibitor 2-deoxyglucose are required to induce cell death in the Th2 lineage. These observations reveal that selection of metabolic pathways for substrate utilization during differentiation of Th1 and Th2 lineages is a fundamental process conserved across species.

Keywords:  CD4+T cell; antibiotics; apoptosis; energy metabolism; mitochondrial translation

DOI:  https://doi.org/10.1111/imm.13860
bioRxiv. 2024 Aug 27. pii: 2024.08.26.609422. [Epub ahead of print]

IRF5 mediates adaptive immunity via altered glutamine metabolism, mTORC1 signaling and post-transcriptional regulation following T cell receptor activation.

Zarina Brune, Ailing Lu, Matthew Moss, Leianna Brune, Amanda Huang, Bharati Matta, Betsy J Barnes.

Although dynamic alterations in transcriptional, translational, and metabolic programs have been described in T cells, the factors and pathways guiding these molecular shifts are poorly understood, with recent studies revealing a disassociation between transcriptional responses and protein expression following T cell receptor (TCR) stimulation. Previous studies identified interferon regulatory factor 5 (IRF5) in the transcriptional regulation of cytokines, chemotactic molecules and T effector transcription factors following TCR signaling. In this study, we identified T cell intrinsic IRF5 regulation of mTORC1 activity as a key modulator of CD40L protein expression. We further demonstrated a global shift in T cell metabolism, with alterations in glutamine metabolism accompanied by shifts in T cell populations at the single cell level due to loss of Irf5. T cell conditional Irf5 knockout mice in a murine model of experimental autoimmune encephalomyelitis (EAE) demonstrated protection from clinical disease with conserved defects in mTORC1 activity and glutamine regulation. Together, these findings expand our mechanistic understanding of IRF5 as an intrinsic regulator of T effector function(s) and support the therapeutic targeting of IRF5 in multiple sclerosis.

DOI: https://doi.org/10.1101/2024.08.26.609422
Int J Mol Sci. 2024 Aug 29. pii: 9364. [Epub ahead of print]25(17):

Metabolic Pathways Affected in Patients Undergoing Hemodialysis and Their Relationship with Inflammation.

María Peris-Fernández, Marta Isabel Roca-Marugán, Julià L Amengual, Ángel Balaguer-Timor, Iris Viejo-Boyano, Amparo Soldevila-Orient, Ramon Devesa-Such, Pilar Sánchez-Pérez, Julio Hernández-Jaras.

  Worldwide, 3.9 million individuals rely on kidney replacement therapy. They experience heightened susceptibility to cardiovascular diseases and mortality, alongside an increased risk of infections and malignancies, with inflammation being key to explaining this intensified risk. This study utilized semi-targeted metabolomics to explore novel metabolic pathways related to inflammation in this population. We collected pre- and post-session blood samples of patients who had already undergone one year of chronic hemodialysis and used liquid chromatography and high-resolution mass spectrometry to perform a metabolomic analysis. Afterwards, we employed both univariate (Mann-Whitney test) and multivariate (logistic regression with LASSO regularization) to identify metabolites associated with inflammation. In the univariate analysis, indole-3-acetaldehyde, 2-ketobutyric acid, and urocanic acid showed statistically significant decreases in median concentrations in the presence of inflammation. In the multivariate analysis, metabolites positively associated with inflammation included allantoin, taurodeoxycholic acid, norepinephrine, pyroglutamic acid, and L-hydroorotic acid. Conversely, metabolites showing negative associations with inflammation included benzoic acid, indole-3-acetaldehyde, methionine, citrulline, alphaketoglutarate, n-acetyl-ornithine, and 3-4-dihydroxibenzeneacetic acid. Non-inflamed patients exhibit preserved autophagy and reduced mitochondrial dysfunction. Understanding inflammation in this group hinges on the metabolism of arginine and the urea cycle. Additionally, the microbiota, particularly uricase-producing bacteria and those metabolizing tryptophan, play critical roles.

Keywords:  metabolic pathways affected in patients undergoing renal replacement therapies; uremic toxins and inflammation

DOI:  https://doi.org/10.3390/ijms25179364
Front Aging. 2024 ;5 1444527

Enhanced mitochondrial function in B cells from elderly type-2 diabetes mellitus patients supports intrinsic inflammation.

Daniela Frasca, Valquiria Bueno.

  In this paper, we measured B cell function in elderly healthy individuals (EH) and in elderly patients with Type-2 Diabetes Mellitus (T2DM, ET2DM), which are treatment-naive, as compared to healthy young (YH) individuals. Results show a higher serum inflammatory status of elderly versus young individuals, and especially of ET2DM versus EH. This status is associated with a reduced response to the seasonal influenza vaccine and with increased frequencies of the circulating pro-inflammatory B cell subset called Double Negative (DN) B cells. B cells from ET2DM patients are not only more inflammatory but also hyper-metabolic as compared to those from EH controls. The results herein are to our knowledge the first to show that T2DM superimposed on aging further increases systemic and B cell intrinsic inflammation, as well as dysfunctional humoral immunity. Our findings confirm and extend our previously published findings showing that inflammatory B cells are metabolically supported.

Keywords:  B cells; aging; inflammation; metabolism; type-2 diabetes mellitus

DOI:  https://doi.org/10.3389/fragi.2024.1444527
Am J Transl Res. 2024 ;16(8): 3480-3497

Itaconate to treat acute lung injury: recent advances and insights from preclinical models.

Qin Juan Wu, Qian Li, Ping Yang, Lei Du.

  Acute lung injury (ALI) is defined as the acute onset of diffuse bilateral pulmonary infiltration, leading to PaO2/FiO2 ≤ 300 mmHg without clinical evidence of left atrial hypertension. Acute respiratory distress syndrome (ARDS) involves more severe hypoxemia (PaO2/FiO2 ≤ 200 mmHg). Treatment of ALI and ARDS has received renewed attention as the incidence of ALI caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has increased. Itaconate and its derivatives have shown therapeutic potential against ALI. This review provides an in-depth summary of the mechanistic research of itaconate in the field of acute lung injury, including inducing autophagy, preventing ferroptosis and pyroptosis, shifting macrophage polarization to an anti-inflammatory M2 phenotype, inhibiting neutrophil activation, regulating epigenetic modifications, and repressing aerobic glycolysis. These compounds merit further consideration in clinical trials. We anticipate that the clinical translation of itaconate-based drugs can be accelerated.

Keywords:  Itaconate; acute lung injury; inflammation; macrophage polarization; neutrophil

DOI:  https://doi.org/10.62347/NUIN2087
mSphere. 2024 Sep 10. e0053424

Time-resolved multi-omics reveals diverse metabolic strategies of Salmonella during diet-induced inflammation.

Katherine Kokkinias, Anice Sabag-Daigle, Yongseok Kim, Ikaia Leleiwi, Michael Shaffer, Richard Kevorkian, Rebecca A Daly, Vicki H Wysocki, Mikayla A Borton, Brian M M Ahmer, Kelly C Wrighton.

  With a rise in antibiotic resistance and chronic infection, the metabolic response of Salmonella enterica serovar Typhimurium to various dietary conditions over time remains an understudied avenue for novel, targeted therapeutics. Elucidating how enteric pathogens respond to dietary variation not only helps us decipher the metabolic strategies leveraged for expansion but also assists in proposing targets for therapeutic interventions. In this study, we use a multi-omics approach to identify the metabolic response of Salmonella enterica serovar Typhimurium in mice on both a fibrous diet and high-fat diet over time. When comparing Salmonella gene expression between diets, we found a preferential use of respiratory electron acceptors consistent with increased inflammation in high-fat diet mice. Looking at the high-fat diet over the course of infection, we noticed heterogeneity in samples based on Salmonella ribosomal activity, which is separated into three infection phases: early, peak, and late. We identified key respiratory, carbon, and pathogenesis gene expressions descriptive of each phase. Surprisingly, we identified genes associated with host cell entry expressed throughout infection, suggesting subpopulations of Salmonella or stress-induced dysregulation. Collectively, these results highlight not only the sensitivity of Salmonella to its environment but also identify phase-specific genes that may be used as therapeutic targets to reduce infection.IMPORTANCEIdentifying novel therapeutic strategies for Salmonella infection that occur in relevant diets and over time is needed with the rise of antibiotic resistance and global shifts toward Western diets that are high in fat and low in fiber. Mice on a high-fat diet are more inflamed compared to those on a fibrous diet, creating an environment that results in more favorable energy generation for Salmonella. We observed differential gene expression across infection phases in mice over time on a high-fat diet. Together, these findings reveal the metabolic tuning of Salmonella to dietary and temporal perturbations. Research like this, which explores the dimensions of pathogen metabolic plasticity, can pave the way for rationally designed strategies to control disease.

Keywords:  CBA/J mice; RNA-seq; microbial metabolism; pathogenesis; respiration; time series

DOI:  https://doi.org/10.1128/msphere.00534-24
Mol Med. 2024 Sep 10. 30(1): 143

IDH2 regulates macrophage polarization and tumorigenesis by modulating mitochondrial metabolism in macrophages.

Sung Woo Lee, Soyoon Kim, Bokyung Kim, Jung Bae Seong, Young-Ho Park, Hong Jun Lee, Dong Kyu Choi, Eunbyul Yeom, Dong-Seok Lee.

   BACKGROUND: Targeting the tumor microenvironment represents an emerging therapeutic strategy for cancer. Macrophages are an essential part of the tumor microenvironment. Macrophage polarization is modulated by mitochondrial metabolism, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and reactive oxygen species content. Isocitrate dehydrogenase 2 (IDH2), an enzyme involved in the TCA cycle, reportedly promotes cancer progression. However, the mechanisms through which IDH2 influences macrophage polarization and modulates tumor growth remain unknown.
METHODS: In this study, IDH2-deficient knockout (KO) mice and primary cultured bone marrow-derived macrophages (BMDMs) were used. Both in vivo subcutaneous tumor experiments and in vitro co-culture experiments were performed, and samples were collected for analysis. Western blotting, RNA quantitative analysis, immunohistochemistry, and flow cytometry were employed to confirm changes in mitochondrial function and the resulting polarization of macrophages exposed to the tumor microenvironment. To analyze the effect on tumor cells, subcutaneous tumor size was measured, and growth and metastasis markers were identified.
RESULTS: IDH2-deficient macrophages co-cultured with cancer cells were found to possess increased mitochondrial dysfunction and fission than wild-type BMDM. Additionally, the levels of M2-associated markers decreased, whereas M1-associated factor levels increased in IDH2-deficient macrophages. IDH2-deficient macrophages were predominantly M1. Tumor sizes in the IDH2-deficient mouse group were significantly smaller than in the wild-type mouse group. IDH2 deficiency in macrophages was associated with inhibited tumor growth and epithelial-mesenchymal transition.
CONCLUSIONS: Our findings suggest that IDH2 deficiency inhibits M2 macrophage polarization and suppresses tumorigenesis. This study underlines the potential contribution of IDH2 expression in macrophages and tumor microenvironment remodeling, which could be useful in clinical cancer research.

Keywords:  Cancer; Isocitrate dehydrogenase 2; Macrophage polarization; Mitochondria; Tumor microenvironment

DOI:  https://doi.org/10.1186/s10020-024-00911-x
Nat Commun. 2024 Sep 10. 15(1): 7914

A mouse protozoan boosts antigen-specific mucosal IgA responses in a specific lipid metabolism- and signaling-dependent manner.

Yanbo Kou, Shenghan Zhang, Junru Chen, Yusi Shen, Zhiwei Zhang, Haohan Huang, Yulu Ma, Yaoyao Xiang, Longxiang Liao, Junyang Zhou, Wanpeng Cheng, Yuan Zhou, Huan Yang, Zhuanzhuan Liu, Yanxia Wei, Hui Wang, Yugang Wang.

IgA antibodies play an important role in mucosal immunity. However, there is still no effective way to consistently boost mucosal IgA responses, and the factors influencing these responses are not fully understood. We observed that colonization with the murine intestinal symbiotic protozoan Tritrichomonas musculis (T.mu) boosted antigen-specific mucosal IgA responses in wild-type C57BL/6 mice. This enhancement was attributed to the accumulation of free arachidonic acid (ARA) in the intestinal lumen, which served as a signal to stimulate the production of antigen-specific mucosal IgA. When ARA was prevented from undergoing its downstream metabolic transformation using the 5-lipoxygenase inhibitor zileuton or by blocking its downstream biological signaling through genetic deletion of the Leukotriene B4 receptor 1 (Blt1), the T.mu-mediated enhancement of antigen-specific mucosal IgA production was suppressed. Moreover, both T.mu transfer and dietary supplementation of ARA augmented the efficacy of an oral vaccine against Salmonella infection, with this effect being dependent on Blt1. Our findings elucidate a tripartite circuit linking nutrients from the diet or intestinal microbiota, host lipid metabolism, and the mucosal humoral immune response.

DOI: https://doi.org/10.1038/s41467-024-52336-z
Nat Cell Biol. 2024 Sep 11.

Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells.

Huafeng Zhang, Jincheng Liu, Wu Yuan, Qian Zhang, Xiao Luo, Yonggang Li, Yue'e Peng, Jingyu Feng, Xiaoyu Liu, Jie Chen, Yabo Zhou, Jiadi Lv, Nannan Zhou, Jingwei Ma, Ke Tang, Bo Huang.

Ammonia is thought to be a cytotoxin and its increase in the blood impairs cell function. However, whether and how this toxin triggers cell death under pathophysiological conditions remains unclear. Here we show that ammonia induces a distinct form of cell death in effector T cells. We found that rapidly proliferating T cells use glutaminolysis to release ammonia in the mitochondria, which is then translocated to and stored in the lysosomes. Excessive ammonia accumulation increases lysosomal pH and results in the termination of lysosomal ammonia storage and ammonia reflux into mitochondria, leading to mitochondrial damage and cell death, which is characterized by lysosomal alkalization, mitochondrial swelling and impaired autophagic flux. Inhibition of glutaminolysis or blocking lysosomal alkalization prevents ammonia-induced T cell death and improves T cell-based antitumour immunotherapy. These findings identify a distinct form of cell death that differs from previously known mechanisms.

DOI: https://doi.org/10.1038/s41556-024-01503-x
Mol Med. 2024 Sep 12. 30(1): 149

Branched-chain amino acids supplementation induces insulin resistance and pro-inflammatory macrophage polarization via INFGR1/JAK1/STAT1 signal pathway.

Huaying Huang, Heye Chen, Yu Yao, Xueyong Lou.

   BACKGROUND: Obesity is a global epidemic, and the low-grade chronic inflammation of adipose tissue in obese individuals can lead to insulin resistance and type 2 diabetes. Adipose tissue macrophages (ATMs) are the main source of pro-inflammatory cytokines in adipose tissue, making them an important target for therapy. While branched-chain amino acids (BCAA) have been strongly linked to obesity and type 2 diabetes in humans, the relationship between BCAA catabolism and adipose tissue inflammation is unclear. This study aims to investigate whether disrupted BCAA catabolism influences the function of adipose tissue macrophages and the secretion of pro-inflammatory cytokines in adipose tissue, and to determine the underlying mechanism. This research will help us better understand the role of BCAA catabolism in adipose tissue inflammation, obesity, and type 2 diabetes.
METHODS: In vivo, we examined whether the BCAA catabolism in ATMs was altered in high-fat diet-induced obesity mice, and if BCAA supplementation would influence obesity, glucose tolerance, insulin sensitivity, adipose tissue inflammation and ATMs polarization in mice. In vitro, we isolated ATMs from standard chow and high BCAA-fed group mice, using RNA-sequencing to investigate the potential molecular pathway regulated by BCAA accumulation. Finally, we performed targeted gene silence experiment and used immunoblotting assays to verify our findings.
RESULTS: We found that BCAA catabolic enzymes in ATMs were influenced by high-fat diet induced obesity mice, which caused the accumulation of both BCAA and its downstream BCKA. BCAA supplementation will cause obesity and insulin resistance compared to standard chow (STC) group. And high BCAA diet will induce pro-inflammatory cytokines including Interlukin-1beta (IL-1β), Tumor Necrosis Factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) secretion in adipose tissue as well as promoting ATMs M1 polarization (pro-inflammatory phenotype). Transcriptomic analysis revealed that a high BCAA diet would activate IFNGR1/JAK1/STAT1 pathway, and IFNGR1 specific silence can abolish the effect of BCAA supplementation-induced inflammation and ATMs M1 polarization.
CONCLUSIONS: The obesity mice model reveals the catabolism of BCAA was disrupted which will cause the accumulation of BCAA, and high-level BCAA will promote ATMs M1 polarization and increase the pro-inflammatory cytokines in adipose tissue which will cause the insulin resistance in further. Therefore, reducing the circulating level of BCAA can be a therapeutic strategy in obesity and insulin resistance patients.

Keywords:  Adipose tissue inflammation; Branched-amino acids; INFGR1/JAK1/STAT1 pathway; Insulin resistance; Obesity; Pro-inflammatory macrophage polarization

DOI:  https://doi.org/10.1186/s10020-024-00894-9