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

Carolin K Koss,Peter J Barnes,Meera Ramanujam,Louise E Donnelly,Jay Fine,Carmen Lerner,Matthew Thomas,Christian T Wohnhaas,Silvia Frey,Cara M M Williams,Cornelia Tilp,Martina Keck,Jonathan R Baker,Michèl Przibilla,Daniel Peter,Karim C El Kasmi,Florian Gantner

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.

Highlights

IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation
These experiments indicated that IL-36 receptor signaling was an upstream driver of neutrophil recruitment and activation in mice exposed to cigarette smoke (CS) smoke
Here, we combined chronic and acute lung inflammation mouse models induced by CS, viral (poly(I:C)), and bacterial (LPS) components with additional in vivo and in vitro approaches using primary mouse and human cells to provide mechanistic insight that identifies IL-36 within the IL-1 family of cytokines as an early upstream innate immune driver and amplifier of acute and chronic lung inflammation, when associated with neutrophils

Summary

Introduction

IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. IL-36 plays an important role in the joint synovium of patients with rheumatoid arthritis[23,24] These studies have extended IL-36 and IL-36R expression to include fibroblasts and macrophages[25,26,27,28], and some reports have suggested IL36 expression by lung epithelial cells[29,30]. Associative data have linked IL-36 cytokine (s) to neutrophilic inflammation in multiple diseased tissues, yet the mechanisms by which IL-36 drives pathology remain elusive We used both wild-type (WT) and knockout (KO) in vitro and in vivo murine experimental approaches together with primary human cells to deconvolute the network of stimuli and responses that orchestrate neutrophilic lung disease. We provide the mechanistic rationale by which targeting IL-36 may alleviate our most burdensome respiratory diseases

Methods

Results

Conclusion