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1. Network analysis of large-scale ImmGen and Tabula Muris datasets highlights metabolic diversity of tissue mononuclear phagocytes.

Author

Gainullina A, Mogilenko DA, Huang LH, Todorov H, Narang V, Kim KW, Yng LS, Kent A, Jia B, Seddu K, Krchma K, Wu J, Crozat K, Tomasello E, Dress R, See P, Scott C, Gibbings S, Bajpai G, Desai JV, Maier B, This S, Wang P, Aguilar SV, Poupel L, Dussaud S, Zhou TA, Angeli V, Blander JM, Choi K, Dalod M, Dzhagalov I, Gautier EL, Jakubzick C, Lavine K, Lionakis MS, Paidassi H, Sieweke MH, Ginhoux F, Guilliams M, Benoist C, Merad M, Randolph GJ, Sergushichev A, and Artyomov MN

Subjects
Animals, Mice, Phagocytes, Single-Cell Analysis
Abstract

The diversity of mononuclear phagocyte (MNP) subpopulations across tissues is one of the key physiological characteristics of the immune system. Here, we focus on understanding the metabolic variability of MNPs through metabolic network analysis applied to three large-scale transcriptional datasets: we introduce (1) an ImmGen MNP open-source dataset of 337 samples across 26 tissues; (2) a myeloid subset of ImmGen Phase I dataset (202 MNP samples); and (3) a myeloid mouse single-cell RNA sequencing (scRNA-seq) dataset (51,364 cells) assembled based on Tabula Muris Senis. To analyze such large-scale datasets, we develop a network-based computational approach, genes and metabolites (GAM) clustering, for unbiased identification of the key metabolic subnetworks based on transcriptional profiles. We define 9 metabolic subnetworks that encapsulate the metabolic differences within MNP from 38 different tissues. Obtained modules reveal that cholesterol synthesis appears particularly active within the migratory dendritic cells, while glutathione synthesis is essential for cysteinyl leukotriene production by peritoneal and lung macrophages., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2023
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2. Itaconate confers tolerance to late NLRP3 inflammasome activation.

Author

Bambouskova M, Potuckova L, Paulenda T, Kerndl M, Mogilenko DA, Lizotte K, Swain A, Hayes S, Sheldon RD, Kim H, Kapadnis U, Ellis AE, Isaguirre C, Burdess S, Laha A, Amarasinghe GK, Chubukov V, Roddy TP, Diamond MS, Jones RG, Simons DM, and Artyomov MN

Subjects
Adenosine Triphosphate pharmacology, Animals, Caspase 1 metabolism, Hydro-Lyases deficiency, Hydro-Lyases genetics, Hydro-Lyases metabolism, Inflammasomes metabolism, Interleukin-1beta metabolism, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Lipopolysaccharides pharmacology, Macrophages cytology, Macrophages drug effects, Macrophages metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Nitric Oxide Synthase Type II metabolism, Phosphate-Binding Proteins genetics, Phosphate-Binding Proteins metabolism, Poly I-C pharmacology, Pyroptosis drug effects, Sepsis chemically induced, Sepsis metabolism, Sepsis pathology, Signal Transduction drug effects, Toll-Like Receptors chemistry, Toll-Like Receptors metabolism, Inflammasomes drug effects, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Succinates pharmacology
Abstract

Itaconate is a unique regulatory metabolite that is induced upon Toll-like receptor (TLR) stimulation in myeloid cells. Here, we demonstrate major inflammatory tolerance and cell death phenotypes associated with itaconate production in activated macrophages. We show that endogenous itaconate is a key regulator of the signal 2 of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation after long lipopolysaccharide (LPS) priming, which establishes tolerance to late NLRP3 inflammasome activation. We show that itaconate acts synergistically with inducible nitric oxide synthase (iNOS) and that the ability of various TLR ligands to establish NLRP3 inflammasome tolerance depends on the pattern of co-expression of IRG1 and iNOS. Mechanistically, itaconate accumulation upon prolonged inflammatory stimulation prevents full caspase-1 activation and processing of gasdermin D, which we demonstrate to be post-translationally modified by endogenous itaconate. Altogether, our data demonstrate that metabolic rewiring in inflammatory macrophages establishes tolerance to NLRP3 inflammasome activation that, if uncontrolled, can result in pyroptotic cell death and tissue damage., Competing Interests: Declaration of interests K.L., S.H., H.K., U.K., V.C., T.P.R., and D.M.S. are employees of Agios Pharmaceuticals. M.S.D. is a consultant for Inbios, Eli Lilly, Vir Biotechnology, and NGM Biopharmaceuticals; is on the Scientific Advisory Board of Moderna; and has received laboratory funding under unrelated sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. All other authors declare no competing financial interest., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2021
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