bims-imicid 2021-09-26 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2021‒09‒26
fourteen papers selected by
Dylan Ryan
University of Cambridge

Itaconate regulates macrophage function through stressful iron-sulfur cluster disrupting and iron metabolism rebalancing.
A20 deficiency in myeloid cells protects mice from diet-induced obesity and insulin resistance due to increased fatty acid metabolism.
Pyruvate Dehydrogenase Kinase Inhibitor Dichloroacetate Improves Host Control of Salmonella enterica Serovar Typhimurium Infection in Human Macrophages.
Salmonella Typhimurium impairs glycolysis-mediated acidification of phagosomes to evade macrophage defense.
Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming.
Soluble carrier transporters and mitochondria in the immunometabolic regulation of macrophages.
Innate immune detection of lipid oxidation as a threat assessment strategy.
Elevated glycolysis imparts functional ability to CD8+ T cells in HIV infection.
Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK.
Selective Induction of Cell Death in Human M1 Macrophages by Smac Mimetics Is Mediated by cIAP-2 and RIPK-1/3 through the Activation of mTORC.
Understanding the heterogeneity and functions of metabolic tissue macrophages.
Interleukin-6 mediates PSAT1 expression and serine metabolism in TSC2-deficient cells.
TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis.
Macrophage IRX3 promotes diet-induced obesity and metabolic inflammation.

FASEB J. 2021 Oct;35(10): e21936

Itaconate regulates macrophage function through stressful iron-sulfur cluster disrupting and iron metabolism rebalancing.

Xing Liu, Bingshuo Shi, Rong Suo, Shenglin Xiong, Xuewen Wang, Xue Liang, Xinjian Li, Guangping Li.

  Lipopolysaccharide (LPS)-stimulated macrophages express an aconitate decarboxylase (IRG1, also called ACOD1), leading to accumulation of the endogenous metabolite itaconate. However, the precise mechanisms by which elevated itaconate levels alter macrophage function are not clear. Our hypothesis is itaconate affects macrophage function through some uncertain mechanism. Based on this, we established a transcriptional and proteomic signature of macrophages stimulated by itaconate and identified the pathways of IL-1β secretion and altered iron metabolism. Consistently, the effect of IRG1 deficiency on IL-1β secretion and iron metabolism was confirmed in IRG1 knockout THP-1 cell lines. Several common inhibitors and other compounds were used to examine the molecular mechanisms involved. Only cysteine and antioxidants (catechin hydrate) could inhibit caspase-1 activation and IL-1β secretion in itaconate-stimulated macrophages. We further found that aconitase activity was decreased by itaconate stimulation. Our results demonstrate the counteracting effects of overexpression of mitochondrial aconitase (ACO2, a tricarboxylic acid cycle enzyme) or cytosolic aconitase (ACO1, an iron regulatory protein) on IL-1β secretion and altered iron metabolism. Both enzyme activities were inhibited by itaconate because of iron-sulfur (Fe-S) cluster destruction. Our findings indicate that the immunoregulatory functions of IRG1 and itaconate in macrophages are stressful Fe-S cluster of aconitases disrupting and iron metabolism rebalancing.

Keywords:  IL-1β; IRG1; aconitase; iron metabolism; iron-sulfur cluster; itaconate

DOI:  https://doi.org/10.1096/fj.202100726RR
Cell Rep. 2021 Sep 21. pii: S2211-1247(21)01202-X. [Epub ahead of print]36(12): 109748

A20 deficiency in myeloid cells protects mice from diet-induced obesity and insulin resistance due to increased fatty acid metabolism.

Leen Catrysse, Bastiaan Maes, Parul Mehrotra, Arne Martens, Esther Hoste, Liesbet Martens, Christian Maueröder, Anneleen Remmerie, Anna Bujko, Karolina Slowicka, Mozes Sze, Hanna Vikkula, Bart Ghesquière, Charlotte L Scott, Yvan Saeys, Bart van de Sluis, Kodi Ravichandran, Sophie Janssens, Geert van Loo.

Obesity-induced inflammation is a major driving force in the development of insulin resistance, type 2 diabetes (T2D), and related metabolic disorders. During obesity, macrophages accumulate in the visceral adipose tissue, creating a low-grade inflammatory environment. Nuclear factor κB (NF-κB) signaling is a central coordinator of inflammatory responses and is tightly regulated by the anti-inflammatory protein A20. Here, we find that myeloid-specific A20-deficient mice are protected from diet-induced obesity and insulin resistance despite an inflammatory environment in their metabolic tissues. Macrophages lacking A20 show impaired mitochondrial respiratory function and metabolize more palmitate both in vitro and in vivo. We hypothesize that A20-deficient macrophages rely more on palmitate oxidation and metabolize the fat present in the diet, resulting in a lean phenotype and protection from metabolic disease. These findings reveal a role for A20 in regulating macrophage immunometabolism.

DOI: https://doi.org/10.1016/j.celrep.2021.109748
Front Immunol. 2021 ;12 739938

Pyruvate Dehydrogenase Kinase Inhibitor Dichloroacetate Improves Host Control of Salmonella enterica Serovar Typhimurium Infection in Human Macrophages.

Cassandra L R van Doorn, Gina K Schouten, Suzanne van Veen, Kimberley V Walburg, Jeroen J Esselink, Matthias T Heemskerk, Frank Vrieling, Tom H M Ottenhoff.

  Global increases in the prevalence of antimicrobial resistance highlight the urgent need for novel strategies to combat infectious diseases. Recent studies suggest that host metabolic pathways play a key role in host control of intracellular bacterial pathogens. In this study we explored the potential of targeting host metabolic pathways for innovative host-directed therapy (HDT) against intracellular bacterial infections. Through gene expression profiling in human macrophages, pyruvate metabolism was identified as potential key pathway involved in Salmonella enterica serovar Typhimurium (Stm) infections. Next, the effect of targeting pyruvate dehydrogenase kinases (PDKs) - which are regulators of the metabolic checkpoint pyruvate dehydrogenase complex (PDC) - on macrophage function and bacterial control was studied. Chemical inhibition of PDKs by dichloroacetate (DCA) induced PDC activation and was accompanied with metabolic rewiring in classically activated macrophages (M1) but not in alternatively activated macrophages (M2), suggesting cell-type specific effects of dichloroacetate on host metabolism. Furthermore, DCA treatment had minor impact on cytokine and chemokine secretion on top of infection, but induced significant ROS production by M1 and M2. DCA markedly and rapidly reduced intracellular survival of Stm, but interestingly not Mycobacterium tuberculosis, in human macrophages in a host-directed manner. In conclusion, DCA represents a promising novel HDT compound targeting pyruvate metabolism for the treatment of Stm infections.

Keywords:  Salmonella typhimurium; dichloroacetate (DCA); host-directed therapy; primary human macrophages; pyruvate dehydrogenase kinase (PDK)

DOI:  https://doi.org/10.3389/fimmu.2021.739938
PLoS Pathog. 2021 Sep 23. 17(9): e1009943

Salmonella Typhimurium impairs glycolysis-mediated acidification of phagosomes to evade macrophage defense.

Saray Gutiérrez, Julia Fischer, Raja Ganesan, Nina Judith Hos, Gökhan Cildir, Martina Wolke, Alberto Pessia, Peter Frommolt, Vincenzo Desiderio, Vidya Velagapudi, Nirmal Robinson.

Regulation of cellular metabolism is now recognized as a crucial mechanism for the activation of innate and adaptive immune cells upon diverse extracellular stimuli. Macrophages, for instance, increase glycolysis upon stimulation with pathogen-associated molecular patterns (PAMPs). Conceivably, pathogens also counteract these metabolic changes for their own survival in the host. Despite this dynamic interplay in host-pathogen interactions, the role of immunometabolism in the context of intracellular bacterial infections is still unclear. Here, employing unbiased metabolomic and transcriptomic approaches, we investigated the role of metabolic adaptations of macrophages upon Salmonella enterica serovar Typhimurium (S. Typhimurium) infections. Importantly, our results suggest that S. Typhimurium abrogates glycolysis and its modulators such as insulin-signaling to impair macrophage defense. Mechanistically, glycolysis facilitates glycolytic enzyme aldolase A mediated v-ATPase assembly and the acidification of phagosomes which is critical for lysosomal degradation. Thus, impairment in the glycolytic machinery eventually leads to decreased bacterial clearance and antigen presentation in murine macrophages (BMDM). Collectively, our results highlight a vital molecular link between metabolic adaptation and phagosome maturation in macrophages, which is targeted by S. Typhimurium to evade cell-autonomous defense.

DOI: https://doi.org/10.1371/journal.ppat.1009943
Cell Metab. 2021 Sep 17. pii: S1550-4131(21)00421-6. [Epub ahead of print]

Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming.

Samantha M Morrissey, Fan Zhang, Chuanlin Ding, Diego Elias Montoya-Durango, Xiaoling Hu, Chenghui Yang, Zhen Wang, Fang Yuan, Matthew Fox, Huang-Ge Zhang, Haixun Guo, David Tieri, Maiying Kong, Corey T Watson, Robert A Mitchell, Xiang Zhang, Kelly M McMasters, Jian Huang, Jun Yan.

  One of the defining characteristics of a pre-metastatic niche, a fundamental requirement for primary tumor metastasis, is infiltration of immunosuppressive macrophages. How these macrophages acquire their phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDEs) polarize macrophages toward an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent, glycolytic-dominant metabolic reprogramming. TDE signaling through TLR2 and NF-κB leads to increased glucose uptake. TDEs also stimulate elevated NOS2, which inhibits mitochondrial oxidative phosphorylation resulting in increased conversion of pyruvate to lactate. Lactate feeds back on NF-κB, further increasing PD-L1. Analysis of metastasis-negative lymph nodes of non-small-cell lung cancer patients revealed that macrophage PD-L1 positively correlates with levels of GLUT-1 and vesicle release gene YKT6 from primary tumors. Collectively, our study provides a novel mechanism by which macrophages within a pre-metastatic niche acquire their immunosuppressive phenotype and identifies an important link among exosomes, metabolism, and metastasis.

Keywords:  NF-kB; PD-L1; exosomes; glycolysis; immunosuppression; lactate; metastasis

DOI:  https://doi.org/10.1016/j.cmet.2021.09.002
Antioxid Redox Signal. 2021 Sep 24.

Soluble carrier transporters and mitochondria in the immunometabolic regulation of macrophages.

Lincon Felipe Lima-Silva, Jennifer Lee, Pedro Moraes Vieira.

SIGNIFICANCE: Immunometabolic regulation of macrophages has been the target of many researchers. Here we review the contribution of solute carriers (SLC) in regulating macrophage metabolism. We also highlight key mechanisms that regulate SLC function, their effects on mitochondrial activity, and how these intracellular activities contribute to macrophage fitness in healthy and disease. Recent Advances: Solute carriers serve as a major drug absorption pathway and represent a novel category of therapeutic drug targets. SLC dynamics affect cellular nutritional sensors, such as AMPK and mTOR and, consequently alters the cellular metabolism and mitochondrial dynamics within macrophages to adapt to a new functional phenotype.CRITICAL ISSUES: Macrophages play a significant role in several pathologies, including insulin resistance, atherosclerosis and cancer. Solute carrier function defines macrophage phenotype and these activities contribute to host health.
FUTURE DIRECTIONS: Few studies focus on the impact of solute transporters on macrophage function. Identifying which solute carriers are present in macrophages and determining their functional roles may reveal novel therapeutic targets with which to treat metabolic and inflammatory diseases.

DOI: https://doi.org/10.1089/ars.2021.0181
Nat Rev Immunol. 2021 Sep 21.

Innate immune detection of lipid oxidation as a threat assessment strategy.

Dania Zhivaki, Jonathan C Kagan.

Oxidized phospholipids that result from tissue injury operate as immunomodulatory signals that, depending on the context, lead to proinflammatory or anti-inflammatory responses. In this Perspective, we posit that cells of the innate immune system use the presence of oxidized lipids as a generic indicator of threat to the host. Similarly to how pathogen-associated molecular patterns represent general indicators of microbial encounters, oxidized lipids may be the most common molecular feature of an injured tissue. Therefore, microbial detection in the absence of oxidized lipids may indicate encounters with avirulent microorganisms. By contrast, microbial detection and detection of oxidized lipids would indicate encounters with replicating microorganisms, thereby inducing a heightened inflammatory and defensive response. Here we review recent studies supporting this idea. We focus on the biology of oxidized phosphocholines, which have emerged as context-dependent regulators of immunity. We highlight emerging functions of oxidized phosphocholines in dendritic cells and macrophages that drive unique inflammasome and migratory activities and hypermetabolic states. We describe how these lipids hyperactivate dendritic cells to stimulate antitumour CD8+ T cell immunity and discuss the potential implications of the newly described activities of oxidized phosphocholines in host defence.

DOI: https://doi.org/10.1038/s41577-021-00618-8
Life Sci Alliance. 2021 Nov;pii: e202101081. [Epub ahead of print]4(11):

Elevated glycolysis imparts functional ability to CD8+ T cells in HIV infection.

Akm Nur-Ur Rahman, Jun Liu, Shariq Mujib, Segen Kidane, Arman Ali, Steven Szep, Carrie Han, Phil Bonner, Michael Parsons, Erika Benko, Colin Kovacs, Feng Yun Yue, Mario Ostrowski.

The mechanisms inducing exhaustion of HIV-specific CD8+ T cells are not fully understood. Metabolic programming directly influences T-cell differentiation, effector function, and memory. We evaluated metabolic profiles of ex vivo CD8+ T cells in HIV-infected individuals. The baseline oxygen consumption rate of CD8+ T cells was elevated in all infected individuals and CD8+ T cells were working at maximal respiratory capacity. The baseline glycolysis rate was enhanced only during early untreated HIV and in viral controllers, but glycolytic capacity was conserved at all stages of infection. CD8+ T-cell mTOR activity was found to be reduced. Enhanced glycolysis was crucial for HIV-specific killing of CD8+ T cells. CD8+ T-cell cytoplasmic GAPDH content was reduced in HIV, but less in early infection and viral controllers. Thus, CD8+ T-cell exhaustion in HIV is characterized by reduced glycolytic activity, enhanced OXPHOS demands, dysregulated mTOR, and reduced cytoplasmic GAPDH. These data provide potential metabolic strategies to reverse CD8+ T-cell dysfunction in HIV.

DOI: https://doi.org/10.26508/lsa.202101081
Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00692-4. [Epub ahead of print]81(18): 3803-3819.e7

Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK.

Che-Chia Hsu, Xian Zhang, Guihua Wang, Weina Zhang, Zhen Cai, Bo-Syong Pan, Haiwei Gu, Chuan Xu, Guoxiang Jin, Xiangshang Xu, Rajesh Kumar Manne, Yan Jin, Wei Yan, Jingwei Shao, Tingjin Chen, Emily Lin, Amit Ketkar, Robert Eoff, Zhi-Gang Xu, Zhong-Zhu Chen, Hong-Yu Li, Hui-Kuan Lin.

  Mitochondrial dynamics regulated by mitochondrial fusion and fission maintain mitochondrial functions, whose alterations underline various human diseases. Here, we show that inositol is a critical metabolite directly restricting AMPK-dependent mitochondrial fission independently of its classical mode as a precursor for phosphoinositide generation. Inositol decline by IMPA1/2 deficiency elicits AMPK activation and mitochondrial fission without affecting ATP level, whereas inositol accumulation prevents AMPK-dependent mitochondrial fission. Metabolic stress or mitochondrial damage causes inositol decline in cells and mice to elicit AMPK-dependent mitochondrial fission. Inositol directly binds to AMPKγ and competes with AMP for AMPKγ binding, leading to restriction of AMPK activation and mitochondrial fission. Our study suggests that the AMP/inositol ratio is a critical determinant for AMPK activation and establishes a model in which AMPK activation requires inositol decline to release AMPKγ for AMP binding. Hence, AMPK is an inositol sensor, whose inactivation by inositol serves as a mechanism to restrict mitochondrial fission.

Keywords:  AMP; AMPK; IMPA1; energy stress; glucose deprivation; inosiotl sensor; inositol; inositol/AMP ratio; mitochondrial fission; mitocondrial dynamics

DOI:  https://doi.org/10.1016/j.molcel.2021.08.025
J Immunol. 2021 Sep 24. pii: ji2100108. [Epub ahead of print]

Selective Induction of Cell Death in Human M1 Macrophages by Smac Mimetics Is Mediated by cIAP-2 and RIPK-1/3 through the Activation of mTORC.

Hamza Ali, Simon Xin Min Dong, Niranjala Gajnayaka, Edana Cassol, Jonathan B Angel, Ashok Kumar.

Inflammatory macrophages have been implicated in many diseases, including rheumatoid arthritis and inflammatory bowel disease. Therefore, targeting macrophage function and activation may represent a potential strategy to treat macrophage-associated diseases. We have previously shown that IFN-γ-induced differentiation of human M0 macrophages toward proinflammatory M1 state rendered them highly susceptible to the cytocidal effects of second mitochondria-derived activator of caspases mimetics (SMs), antagonist of the inhibitors of apoptosis proteins (IAPs), whereas M0 and anti-inflammatory M2c macrophages were resistant. In this study, we investigated the mechanism governing SM-induced cell death during differentiation into M1 macrophages and in polarized M1 macrophages. IFN-γ stimulation conferred on M0 macrophages the sensitivity to SM-induced cell death through the Jak/STAT, IFN regulatory factor-1, and mammalian target of rapamycin complex-1 (mTORC-1)/ribosomal protein S6 kinase pathways. Interestingly, mTORC-1 regulated SM-induced cell death independent of M1 differentiation. In contrast, SM-induced cell death in polarized M1 macrophages is regulated by the mTORC-2 pathway. Moreover, SM-induced cell death is regulated by cellular IAP (cIAP)-2, receptor-interacting protein kinase (RIPK)-1, and RIPK-3 degradation through mTORC activation during differentiation into M1 macrophages and in polarized M1 macrophages. In contrast to cancer cell lines, SM-induced cell death in M1 macrophages is independent of endogenously produced TNF-α, as well as the NF-κB pathway. Collectively, selective induction of cell death in human M1 macrophages by SMs may be mediated by cIAP-2, RIPK-1, and RIPK-3 degradation through mTORC activation. Moreover, blocking cIAP-1/2, mTORC, or IFN regulatory factor-1 may represent a promising therapeutic strategy to control M1-associated diseases.

DOI: https://doi.org/10.4049/jimmunol.2100108
Semin Cell Dev Biol. 2021 Sep 21. pii: S1084-9521(21)00237-8. [Epub ahead of print]

Understanding the heterogeneity and functions of metabolic tissue macrophages.

Amélie Grosjean, Nicolas Venteclef, Elise Dalmas.

  Growing evidence places tissue-resident macrophages as essential gatekeepers of metabolic organ homeostasis, including the adipose tissue and the pancreatic islets. Therein, macrophages may adopt specific phenotypes and ensure local functions. Recent advances in single cell genomic analyses provide a comprehensive map of adipose tissue macrophage subsets and their potential roles are now better apprehended. Whether they are beneficial or detrimental, macrophages overall contribute to the proper adipose tissue expansion under steady state and during obesity. By contrast, macrophages residing inside pancreatic islets, which may exert fundamental functions to fine tune insulin secretion, have only started to attract attention and their cellular heterogeneity remains to be established. The present review will focus on the latest findings exploring the phenotype and the properties of macrophages in adipose tissue and pancreatic islets, questioning early beliefs and future perspectives in the field of immunometabolism.

Keywords:  Adipose tissue; Diabetes; Immunity; Macrophages; Metabolism; Pancreatic islets

DOI:  https://doi.org/10.1016/j.semcdb.2021.09.002
Proc Natl Acad Sci U S A. 2021 09 28. pii: e2101268118. [Epub ahead of print]118(39):

Interleukin-6 mediates PSAT1 expression and serine metabolism in TSC2-deficient cells.

Ji Wang, Harilaos Filippakis, Thomas Hougard, Heng Du, Chenyang Ye, Heng-Jia Liu, Long Zhang, Khadijah Hindi, Shefali Bagwe, Julie Nijmeh, John M Asara, Wei Shi, Souheil El-Chemaly, Elizabeth P Henske, Hilaire C Lam.

  Tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM) are caused by aberrant mechanistic Target of Rapamycin Complex 1 (mTORC1) activation due to loss of either TSC1 or TSC2 Cytokine profiling of TSC2-deficient LAM patient-derived cells revealed striking up-regulation of Interleukin-6 (IL-6). LAM patient plasma contained increased circulating IL-6 compared with healthy controls, and TSC2-deficient cells showed up-regulation of IL-6 transcription and secretion compared to wild-type cells. IL-6 blockade repressed the proliferation and migration of TSC2-deficient cells and reduced oxygen consumption and extracellular acidification. U-13C glucose tracing revealed that IL-6 knockout reduced 3-phosphoserine and serine production in TSC2-deficient cells, implicating IL-6 in de novo serine metabolism. IL-6 knockout reduced expression of phosphoserine aminotransferase 1 (PSAT1), an essential enzyme in serine biosynthesis. Importantly, recombinant IL-6 treatment rescued PSAT1 expression in the TSC2-deficient, IL-6 knockout clones selectively and had no effect on wild-type cells. Treatment with anti-IL-6 (αIL-6) antibody similarly reduced cell proliferation and migration and reduced renal tumors in Tsc2 +/- mice while reducing PSAT1 expression. These data reveal a mechanism through which IL-6 regulates serine biosynthesis, with potential relevance to the therapy of tumors with mTORC1 hyperactivity.

Keywords:  interleukin 6; lymphangioleiomyomatosis; mTORC1; phosphoserine aminotransferase 1 (PSAT1); tuberous sclerosis complex

DOI:  https://doi.org/10.1073/pnas.2101268118
PLoS Pathog. 2021 Sep 24. 17(9): e1009941

TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis.

Jeffrey M Collins, Dean P Jones, Ashish Sharma, Manoj Khadka, Ken H Liu, Russell R Kempker, Brendan Prideaux, Kristal Maner-Smith, Nestani Tukvadze, N Sarita Shah, James C M Brust, Rafick-Pierre Sékaly, Neel R Gandhi, Henry M Blumberg, Eric A Ortlund, Thomas R Ziegler.

The metabolic signaling pathways that drive pathologic tissue inflammation and damage in humans with pulmonary tuberculosis (TB) are not well understood. Using combined methods in plasma high-resolution metabolomics, lipidomics and cytokine profiling from a multicohort study of humans with pulmonary TB disease, we discovered that IL-1β-mediated inflammatory signaling was closely associated with TCA cycle remodeling, characterized by accumulation of the proinflammatory metabolite succinate and decreased concentrations of the anti-inflammatory metabolite itaconate. This inflammatory metabolic response was particularly active in persons with multidrug-resistant (MDR)-TB that received at least 2 months of ineffective treatment and was only reversed after 1 year of appropriate anti-TB chemotherapy. Both succinate and IL-1β were significantly associated with proinflammatory lipid signaling, including increases in the products of phospholipase A2, increased arachidonic acid formation, and metabolism of arachidonic acid to proinflammatory eicosanoids. Together, these results indicate that decreased itaconate and accumulation of succinate and other TCA cycle intermediates is associated with IL-1β-mediated proinflammatory eicosanoid signaling in pulmonary TB disease. These findings support host metabolic remodeling as a key driver of pathologic inflammation in human TB disease.

DOI: https://doi.org/10.1371/journal.ppat.1009941
Nat Immunol. 2021 Sep 23.

Macrophage IRX3 promotes diet-induced obesity and metabolic inflammation.

Jingfei Yao, Dongmei Wu, Chunyan Zhang, Ting Yan, Yiheng Zhao, Hongyu Shen, Kaili Xue, Xun Huang, Zihao Wang, Yifu Qiu.

Metabolic inflammation is closely linked to obesity, and is implicated in the pathogenesis of metabolic diseases. FTO harbors the strongest genetic association with polygenic obesity, and IRX3 mediates the effects of FTO on body weight. However, in what cells and how IRX3 carries out this control are poorly understood. Here we report that macrophage IRX3 promotes metabolic inflammation to accelerate the development of obesity and type 2 diabetes. Mice with myeloid-specific deletion of Irx3 were protected against diet-induced obesity and metabolic diseases via increasing adaptive thermogenesis. Mechanistically, macrophage IRX3 promoted proinflammatory cytokine transcription and thus repressed adipocyte adrenergic signaling, thereby inhibiting lipolysis and thermogenesis. JNK1/2 phosphorylated IRX3, leading to its dimerization and nuclear translocation for transcription. Further, lipopolysaccharide stimulation stabilized IRX3 by inhibiting its ubiquitination, which amplified the transcriptional capacity of IRX3. Together, our findings identify a new player, macrophage IRX3, in the control of body weight and metabolic inflammation, implicating IRX3 as a therapeutic target.

DOI: https://doi.org/10.1038/s41590-021-01023-y