The activation and function of IL-36γ in neutrophilic inflammation in chronic rhinosinusitis

J Allergy Clin Immunol. 2018 May;141(5):1646-1658. doi: 10.1016/j.jaci.2017.12.972. Epub 2017 Dec 21.

Abstract

Background: Although increased accumulation of neutrophils has been noted in chronic rhinosinusitis (CRS), the function and regulation of neutrophils in CRS are largely unknown. IL-36 family cytokines may play an important role in neutrophilic inflammation.

Objective: This study sought to investigate the expression and function of IL-36 cytokines in CRS.

Methods: Quantitative RT-PCR, immunohistochemistry, immunofluorescence, and ELISA were used to investigate the expression of IL-36 cytokines and IL-36 receptor (IL-36R) in sinonasal mucosa. The expression of IL-36R on neutrophils in polyps and blood was measured by flow cytometry. Purified blood neutrophils were cultured to investigate the regulation of IL-36R expression. The cleavage of IL-36γ was detected by Western blotting. Dispersed nasal polyp cells were treated with IL-36γ with or without elastase inhibitor and dexamethasone.

Results: Neutrophil infiltration and expression of IL-36 cytokines and IL-36R were upregulated in both CRS with and without nasal polyps. IL-36γ was the most abundant isoform and mainly expressed by epithelial cells in CRS. Neutrophils were the principal IL-36R+ cell type in polyps. IL-36R expression was almost absent in blood neutrophils and upregulated by IL-6, IL-1β, and Dermatophagoides pteronyssinus group 1. Elastase activity was increased in polyps and degraded full-length IL-36γ. Consistently, the levels of cleaved IL-36γ were increased in polyps. Full-length IL-36γ promoted the production of matrix metalloproteinase 9; IL-17A; and chemokine (C-X-C motif) ligands 1, 2, and 8 from dispersed nasal polyp cells, which was abolished by elastase inhibitor. The proinflammatory effect of IL-36γ was not suppressed by dexamethasone.

Conclusions: Increased production and activation of IL-36γ may act on neutrophils and further exaggerate neutrophilic inflammation in CRS.

Keywords: Activate; IL-17; IL-36; chronic rhinosinusitis; elastase; nasal polyps; neutrophil.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Chronic Disease
  • Cytokines / metabolism
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Gene Expression / physiology
  • Humans
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Interleukin-1 / metabolism*
  • Interleukin-1beta / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Nasal Mucosa / metabolism
  • Nasal Mucosa / pathology
  • Nasal Polyps / metabolism
  • Nasal Polyps / pathology
  • Neutrophils / metabolism*
  • Neutrophils / pathology
  • Receptors, Interleukin-1 / metabolism
  • Rhinitis / metabolism*
  • Rhinitis / pathology
  • Sinusitis / metabolism*
  • Sinusitis / pathology
  • Up-Regulation / physiology

Substances

  • Cytokines
  • IL36G protein, human
  • Interleukin-1
  • Interleukin-1beta
  • Receptors, Interleukin-1
  • Matrix Metalloproteinase 9