Publication
Obesity Potentiates TH2 Immunopathology via Dysregulation of PPARγ
Publisher:
Cold Spring Harbor Laboratory
Date:
31-10-2019
DOI:
10.1101/825836
Abstract: How obesity affects immune function is not well understood. Clinically, obesity is strongly associated with severe T H 2 immunopathology 1-3 , though the physiological, cellular, and molecular underpinnings of this association remain obscure. Here, we demonstrate that obese mice are susceptible to severe atopic dermatitis (AD), a major manifestation of T H 2 immunopathology and disease burden in humans 4,5 . Mechanistically, we show that dysregulation of the nuclear hormone receptor (NHR) PPAR γ (peroxisome proliferator-activated receptor gamma) in T cells is a causal link between obesity and the increased T H 2 immunopathology. We find that PPAR γ oversees a cellular metabolic transcriptional program that restrains nuclear gene expression of the chief T H 2 priming and effector cytokine interleukin-4 (IL-4). Accordingly, thiazolidinediones (TZDs), potent PPAR γ agonists, robustly protect obese mice from T H 2 immunopathology. Collectively, these findings establish PPAR γ as a molecular link between obesity and T H 2 immune homeostasis and identify TZDs as novel therapeutic candidates for T H 2 immunopathology. Fundamentally, these findings demonstrate that shifting physiologic metabolic states can shape the tone of adaptive immune responses to modulate differential disease susceptibility.