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

Front Immunol. 2023 Jan 16:14:1119473. doi: 10.3389/fimmu.2023.1119473. eCollection 2023.

Abstract

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.

Keywords: A20 (TNFAIP3); IAV; NF-κB; NLRP3 inflammasome; PPAR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Inflammation / metabolism
  • Influenza, Human*
  • Lipopolysaccharides / pharmacology
  • NF-kappa B* / metabolism
  • Peroxisome Proliferator-Activated Receptors
  • Tumor Necrosis Factor alpha-Induced Protein 3 / metabolism

Substances

  • NF-kappa B
  • Lipopolysaccharides
  • Peroxisome Proliferator-Activated Receptors
  • Tumor Necrosis Factor alpha-Induced Protein 3

Grants and funding

This work was supported by Key Laboratory of Precision Infectious Diseases of Jilin Province (Grant no.20200601011JC), Jilin Provincial Key Laboratory of Pathogen Biology (Grant no.3D5200117426), Jilin Provincial Development and Reform Commission Common Disease Precision Prevention and Control Engineering Laboratory, Jilin Provincial Science and Technology Innovation Center of Secondary Development of Chinese Traditional Patent Medicine (Grant no.20210502005ZP).