Chronic exposure to low-level lipopolysaccharide dampens influenza-mediated inflammatory response via A20 and PPAR network

• DOI: 10.3389/fimmu.2023.1119473
• Publication Date: 2023-01-16T05:28:15Z
• Authors: Yinuo Gu; Alan Chen-Yu Hsu; Xu Zuo; Xiaoping Guo; Zhengjie Zhou; Shengyu Jiang; Zhuoer Ouyang; Fang Wang
• Keywords: Lipopolysaccharides; Inflammation; 0303 health sciences; Immunology; Peroxisome Proliferator-Activated Receptors; NF-kappa B; RC581-607; PPAR; NF-κB; NLRP3 inflammasome; 3. Good health; IAV; 03 medical and health sciences; NLRP3; inflammasome; Influenza, Human; A20 (TNFAIP3); Humans; NF-kB; Immunologic diseases. Allergy; Tumor Necrosis Factor alpha-Induced Protein 3

Influenza A virus (IAV) infection leads to severe inflammation, and while epithelial-driven inflammatory responses occur via activation of NF-κB, the factors that modulate inflammation, particularly the negative regulators are less well-defined. In this study we show that A20 is a crucial molecular switch that dampens IAV-induced inflammatory responses. Chronic exposure to low-dose LPS environment can restrict this excessive inflammation. The mechanisms that this environment provides to suppress inflammation remain elusive. Here, our evidences show that chronic exposure to low-dose LPS suppressed IAV infection or LPS stimulation-induced inflammation in vitro and in vivo. Chronic low-dose LPS environment increases A20 expression, which in turn positively regulates PPAR-α and -γ, thus dampens the NF-κB signaling pathway and NLRP3 inflammasome activation. Knockout of A20 abolished the inhibitory effect on inflammation. Thus, A20 and its induced PPAR-α and -γ play a key role in suppressing excessive inflammatory responses in the chronic low-dose LPS environment.