IL36 is a critical upstream amplifier of neutrophilic lung inflammation in mice

Commun Biol. 2021 Feb 8;4(1):172. doi: 10.1038/s42003-021-01703-3.

Abstract

IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we combined in vivo and in vitro approaches using primary mouse and human cells, as well as, acute and chronic mouse models of lung inflammation to provide mechanistic insight into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. IL-36 receptor deficient mice exposed to cigarette smoke or cigarette smoke and H1N1 influenza virus had attenuated lung inflammation compared with wild-type controls. We identified neutrophils as a source of IL-36 and show that IL-36 is a key upstream amplifier of lung inflammation by promoting activation of neutrophils, macrophages and fibroblasts through cooperation with GM-CSF and the viral mimic poly(I:C). Our data implicate IL-36, independent of other IL-1 family members, as a key upstream amplifier of neutrophilic lung inflammation, providing a rationale for targeting IL-36 to improve treatment of a variety of neutrophilic lung diseases.

MeSH terms

  • Animals
  • Cells, Cultured
  • Cigarette Smoking
  • Disease Models, Animal
  • Female
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Humans
  • Influenza A Virus, H1N1 Subtype / pathogenicity
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism*
  • Lung / immunology
  • Lung / metabolism*
  • Lung / virology
  • Macrophage Activation
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophil Activation*
  • Neutrophils / immunology
  • Neutrophils / metabolism*
  • Neutrophils / virology
  • Orthomyxoviridae Infections / genetics
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / metabolism*
  • Orthomyxoviridae Infections / virology
  • Pneumonia, Viral / genetics
  • Pneumonia, Viral / immunology
  • Pneumonia, Viral / metabolism*
  • Pneumonia, Viral / virology
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / metabolism*
  • Signal Transduction

Substances

  • IL1F9 protein, mouse
  • Interleukin-1
  • Receptors, Interleukin-1
  • interleukin-36 receptor, mouse