PPARγ Deficiency Suppresses the Release of IL-1β and IL-1α in Macrophages via a Type 1 IFN-Dependent Mechanism

The Journal of Immunology : Official Journal of the American Association of Immunologists
Kassandra J WeberJoel D Schilling

Abstract

Obesity and diabetes modulate macrophage activation, often leading to prolonged inflammation and dysfunctional tissue repair. Increasing evidence suggests that the NLRP3 inflammasome plays an important role in obesity-associated inflammation. We have previously shown that activation of the lipotoxic inflammasome by excess fatty acids in macrophages occurs via a lysosome-dependent pathway. However, the mechanisms that link cellular lipid metabolism to altered inflammation remain poorly understood. PPARγ is a nuclear receptor transcription factor expressed by macrophages that is known to alter lipid handling, mitochondrial function, and inflammatory cytokine expression. To undercover novel links between metabolic signaling and lipotoxic inflammasome activation, we investigated mouse primary macrophages deficient in PPARγ. Contrary to our expectation, PPARγ knockout (KO) macrophages released significantly less IL-1β and IL-1α in response to lipotoxic stimulation. The suppression occurred at the transcriptional level and was apparent for multiple activators of the NLRP3 inflammasome. RNA sequencing revealed upregulation of IFN-β in activated PPARγKO macrophages, and this was confirmed at the protein level. A blocking Ab against the...Continue Reading

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Citations

Jun 6, 2019·Journal of Leukocyte Biology·Gowri KalugotlaJoel D Schilling
Mar 22, 2019·PLoS Pathogens·Chrissy M Leopold WagerLarry S Schlesinger
Aug 17, 2019·Frontiers in Immunology·Manfred KunzAnja Saalbach
Feb 11, 2020·Frontiers in Immunology·Sabine Daemen, Joel D Schilling
Nov 16, 2019·Biomolecules·Yun TianYongming Sang
Mar 16, 2021·Frontiers in Immunology·Ahmad Alatshan, Szilvia Benkő
Aug 18, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Merilin Al Sharif
Nov 11, 2021·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Nicholas DopkinsMitzi Nagarkatti

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