Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages

Runtsch, Marah C.; Angiari, Stefano; Hooftman, Alexander; Wadhwa, Ridhima; Zhang, Yanling; Zheng, Yunan; Spina, Joseph S.; Ruzek, Melanie C.; Argiriadi, M.A.; McGettrick, Anne F.; Mendez, Rui Santalla; Zotta, Alessia; Peace, Christian G.; Walsh, Aoife; Chirillo, Roberta; Hams, Emily; Fallon, Padraic G.; Jayamaran, Ranjith; Dua, Kamal; Brown, Alexandra C.; Kim, Richard; Horvat, Jay C.; Hansbro, Philip M.; Wang, Chu; O’Neill, Luke A.J.

doi:10.1016/j.cmet.2022.02.002

Cited by 161 publications

(114 citation statements)

References 58 publications

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“…Although mechanisms of asthma involving a variety of cytokine mediators have been extensively studied, growing evidence indicates that cellular metabolism also plays an important role ( 17 , 18 ). Targeted and nontargeted metabolomic studies (i.e., focused only on a specific class of molecules vs. interrogation of the entire metabolome) in different human biological compartments have shown that biomarkers related to the tricarboxylic acid (TCA) cycle, hypoxia response, amino acid metabolism (glutamine, l -arginine) and oxidative stress are all associated with asthma diagnosis or with increased asthma morbidity (presenter Fernando Holguin, M.D.)…”

Section: Presentations and Discussionmentioning

confidence: 99%

“…Cellular metabolism could be influenced by the presence of an altered microbiome and extracellular metabolic milieu. The impact of such on the activation and regulation of innate and adaptive immune functions implicated in asthma could be significant on the basis of recent growing evidence ( 17 , 18 ), but human translation of current knowledge remains nascent.…”

Section: Introductionmentioning

confidence: 99%

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Microbiome, Metabolism, and Immunoregulation of Asthma: An American Thoracic Society and National Institute of Allergy and Infectious Diseases Workshop Report

Kozik¹,

Holguín²,

Chatila³

et al. 2022

Am J Respir Cell Mol Biol

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This report presents the proceedings from a workshop titled “Microbiome, Metabolism and Immunoregulation of Asthma” that was held virtually May 13 and 14, 2021. The workshop was jointly sponsored by the American Thoracic Society (Assembly on Allergy, Immunology, and Inflammation) and the National Institute of Allergy and Infectious Diseases. It convened an interdisciplinary group of experts with backgrounds in asthma immunology, microbiome science, metabolomics, computational biology, and translational pulmonary research. The main purpose was to identify key scientific gaps and needs to further advance research on microbial and metabolic mechanisms that may contribute to variable immune responses and disease heterogeneity in asthma. Discussions were structured around several topics, including 1 ) immune and microbial mechanisms of asthma pathogenesis in murine models, 2 ) the role of microbes in pediatric asthma exacerbations, 3 ) dysregulated metabolic pathways in asthma associated with obesity, 4 ) metabolism effects on macrophage function in adipose tissue and the lungs, 5 ) computational approaches to dissect microbiome–metabolite links, and 6 ) potential confounders of microbiome–disease associations in human studies. This report summarizes the major points of discussion, which included identification of specific knowledge gaps, challenges, and suggested directions for future research. These include questions surrounding mechanisms by which microbiota and metabolites shape host health versus an allergic or asthmatic state; direct and indirect influences of other biological factors, exposures, and comorbidities on these interactions; and ongoing technical and analytical gaps for clinical translation.

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Section: Presentations and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Microbiome, Metabolism, and Immunoregulation of Asthma: An American Thoracic Society and National Institute of Allergy and Infectious Diseases Workshop Report

Kozik¹,

Holguín²,

Chatila³

et al. 2022

Am J Respir Cell Mol Biol

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show abstract

“…However, the high polarity and low electrophilicity of unmodified itaconate confer it weak cell permeability to fulfill therapeutic purposes. Therefore, itaconate-based therapeutic efforts have focused on developing derivatives, which could be potent and safe pharmacological agents to treat inflammatory disorders [ 181 ]. Indeed, itaconate derivative dimethyl itaconate (DI) exhibits high membrane-permeable ability and, importantly, marked acceptor reactivity, which causes potent NRF2 activation and the significant depletion of glutathione levels [ 182 ].…”

Section: Modulating Macrophage Function By Redox Signals: a Therapeut...mentioning

confidence: 99%

Macrophage Polarization and Reprogramming in Acute Inflammation: A Redox Perspective

2022

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Macrophage polarization refers to the process by which macrophages can produce two distinct functional phenotypes: M1 or M2. The balance between both strongly affects the progression of inflammatory disorders. Here, we review how redox signals regulate macrophage polarization and reprogramming during acute inflammation. In M1, macrophages augment NADPH oxidase isoform 2 (NOX2), inducible nitric oxide synthase (iNOS), synaptotagmin-binding cytoplasmic RNA interacting protein (SYNCRIP), and tumor necrosis factor receptor-associated factor 6 increase oxygen and nitrogen reactive species, which triggers inflammatory response, phagocytosis, and cytotoxicity. In M2, macrophages down-regulate NOX2, iNOS, SYNCRIP, and/or up-regulate arginase and superoxide dismutase type 1, counteract oxidative and nitrosative stress, and favor anti-inflammatory and tissue repair responses. M1 and M2 macrophages exhibit different metabolic profiles, which are tightly regulated by redox mechanisms. Oxidative and nitrosative stress sustain the M1 phenotype by activating glycolysis and lipid biosynthesis, but by inhibiting tricarboxylic acid cycle and oxidative phosphorylation. This metabolic profile is reversed in M2 macrophages because of changes in the redox state. Therefore, new therapies based on redox mechanisms have emerged to treat acute inflammation with positive results, which highlights the relevance of redox signaling as a master regulator of macrophage reprogramming.

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“…9 , 35 in humans. Beyond its antimicrobial activity itaconate is also known as an immunomodulatory metabolite 45 , 52 . Thus, one could speculate that some of TFEB’s reported anti-inflammatory and immunomodulatory effects may act through control of itaconate 18 , 53 .…”

Section: Mainmentioning

confidence: 99%

TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages

et al. 2022

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Successful elimination of bacteria in phagocytes occurs in the phago-lysosomal system, but also depends on mitochondrial pathways. Yet, how these two organelle systems communicate is largely unknown. Here we identify the lysosomal biogenesis factor transcription factor EB (TFEB) as regulator for phago-lysosome-mitochondria crosstalk in macrophages. By combining cellular imaging and metabolic profiling, we find that TFEB activation, in response to bacterial stimuli, promotes the transcription of aconitate decarboxylase (Acod1, Irg1) and synthesis of its product itaconate, a mitochondrial metabolite with antimicrobial activity. Activation of the TFEB–Irg1–itaconate signalling axis reduces the survival of the intravacuolar pathogen Salmonella enterica serovar Typhimurium. TFEB-driven itaconate is subsequently transferred via the Irg1-Rab32–BLOC3 system into the Salmonella-containing vacuole, thereby exposing the pathogen to elevated itaconate levels. By activating itaconate production, TFEB selectively restricts proliferating Salmonella, a bacterial subpopulation that normally escapes macrophage control, which contrasts TFEB’s role in autophagy-mediated pathogen degradation. Together, our data define a TFEB-driven metabolic pathway between phago-lysosomes and mitochondria that restrains Salmonella Typhimurium burden in macrophages in vitro and in vivo.

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Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages

Cited by 161 publications

References 58 publications

Microbiome, Metabolism, and Immunoregulation of Asthma: An American Thoracic Society and National Institute of Allergy and Infectious Diseases Workshop Report

Microbiome, Metabolism, and Immunoregulation of Asthma: An American Thoracic Society and National Institute of Allergy and Infectious Diseases Workshop Report

Macrophage Polarization and Reprogramming in Acute Inflammation: A Redox Perspective

TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages

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