PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism

Genes & Development
Victoria L NelsonM A Lazar

Abstract

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that peritoneal macrophage respiration is enhanced by rosiglitazone, an activating PPARγ ligand, in a PPARγ-dependent manner. Moreover, PPARγ is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPARγ dramatically affects the oxidation of glutamine. Both glutamine and PPARγ have been implicated in alternative activation (AA) of macrophages, and PPARγ was required for interleukin 4 (IL4)-dependent gene expression and stimulation of macrophage respiration. Indeed, unstimulated macrophages lacking PPARγ contained elevated levels of the inflammation-associated metabolite itaconate and express a proinflammatory transcriptome that, remarkably, phenocopied that of macrophages depleted of glutamine. Thus, PPARγ functions as a checkpoint, guarding against inflammation, and is permissive for AA by facilitating glutamine metabolism. However, PPARγ expression is itself markedly increased by IL4. This suggests that PPARγ functions at the center of a feed-forward loop that is central to AA of macrophages.

References

May 29, 2004·Trends in Pharmacological Sciences·Shamina M Rangwala, Mitchell A Lazar
Oct 12, 2004·Annual Review of Cell and Developmental Biology·Antonio Castrillo, Peter Tontonoz
Jun 11, 2005·Arteriosclerosis, Thrombosis, and Vascular Biology·Vladimir R BabaevMacRae F Linton
Feb 21, 2008·Molecular and Cellular Biology·David J StegerChristopher R Vakoc
Mar 6, 2009·Genome Biology·Ben LangmeadSteven L Salzberg
Feb 24, 2010·Molecular and Cellular Biology·Martina I LefterovaMitchell A Lazar
May 29, 2010·Circulation Research·Ajay Chawla
Nov 6, 2010·Analytical Chemistry·Eugene MelamudJoshua D Rabinowitz
Sep 17, 2011·Journal of the American Chemical Society·Cheryl L StrelkoMary F Roberts
Mar 21, 2013·Proceedings of the National Academy of Sciences of the United States of America·Ajit S DivakaruniAnne N Murphy
Apr 24, 2013·Proceedings of the National Academy of Sciences of the United States of America·Alessandro MichelucciKarsten Hiller
Jul 23, 2013·Nature Protocols·Huaiyu MiPaul D Thomas
Sep 23, 2014·Cell Metabolism·Raymond E SoccioMitchell A Lazar
Mar 19, 2015·Immunity·Luke A J O'Neill
Feb 18, 2016·Nature Immunology·Mitsunori NomuraToren Finkel
May 18, 2016·The Journal of Biological Chemistry·Thekla CordesChristian M Metallo
Jun 9, 2016·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Søren Fisker SchmidtSusanne Mandrup
Feb 23, 2017·American Journal of Physiology. Endocrinology and Metabolism·Elsie Gonzalez-HurtadoMichael J Wolfgang
Feb 28, 2017·The Journal of Clinical Investigation·Raymond E SoccioMitchell A Lazar
Jun 9, 2017·Clinical Science·Rui CuriPhilip Newsholme
Jun 28, 2017·Annual Review of Biochemistry·Wenyun LuJoshua D Rabinowitz

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Citations

Apr 4, 2020·Immunological Reviews·Nikki van Teijlingen Bakker, Edward J Pearce
Jan 28, 2020·Annual Review of Immunology·Dylan G Ryan, Luke A J O'Neill
Jul 12, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Ye ZhangXianjing Li
Oct 27, 2018·Nutrients·Vinicius CruzatPhilip Newsholme
Feb 26, 2020·Animals : an Open Access Journal From MDPI·Ali Mujtaba ShahJian Ma
Feb 2, 2019·Nature Reviews. Immunology·Luke A J O'Neill, Maxim N Artyomov
Jan 31, 2020·Frontiers in Immunology·Ana Batista-GonzalezLeandro J Carreño
May 10, 2020·International Immunology·Michio Miyajima
Aug 28, 2020·Frontiers in Immunology·George A TimmonsJames O Early
Jun 20, 2019·Nature Immunology·Gioacchino Natoli, Renato Ostuni
Jul 3, 2020·Immunology·Diana Cortes-Selva, Keke Fairfax
Jan 14, 2021·Experimental Neurology·Atsushi Mizuma, Midori A Yenari
Feb 9, 2020·Gastroenterology Clinics of North America·Manu V ChakravarthyNicola Guess
Jan 8, 2021·Biomarker Research·Yang LiuZhen Cai
Nov 11, 2020·Current Opinion in Immunology·Ajoy AloysiusAshley W Seifert
Mar 3, 2021·Genes & Development·Yun Sok Lee, Jerrold Olefsky
Apr 4, 2021·Nutrients·Jian TanLaurence Macia
Jun 9, 2021·Nature Immunology·Samuel A RoseUNKNOWN Immunological Genome Consortium
Jun 16, 2021·Nature Reviews. Cardiology·David MontaigneBart Staels
Aug 6, 2021·Frontiers in Cellular and Infection Microbiology·Amy A O'CallaghanSinéad C Corr
Aug 8, 2021·International Journal of Molecular Sciences·Maaike Suuring, Aurélie Moreau
Jul 31, 2021·EMBO Reports·Gioacchino NatoliSerena Ghisletti
Aug 31, 2021·Frontiers in Immunology·Marie Jo Halaby, Tracy L McGaha
Sep 5, 2021·The FEBS Journal·Wenfeng ZengWei Liang

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