IL-36 receptor deletion attenuates lung injury and decreases mortality in murine influenza pneumonia

T. Aoyagi, M. W. Newstead, X. Zeng, S. L. Kunkel, M. Kaku, T. J. Standiford

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

Influenza virus causes a respiratory disease in humans that can progress to lung injury with fatal outcome. The interleukin (IL)-36 cytokines are newly described IL-1 family cytokines that promote inflammatory responses via binding to the IL-36 receptor (IL-36R). The mechanism of expression and the role of IL-36 cytokines are poorly understood. Here, we investigated the role of IL-36 cytokines in modulating the innate inflammatory response during influenza virus-induced pneumonia in mice. The intranasal administration of influenza virus upregulated IL-36α mRNA and protein production in the lungs. In vitro, influenza virus-mediated IL-36α but not IL-36γ is induced and secreted from alveolar epithelial cells (AECs) through both a caspase-1 and caspase-3/7 dependent pathway. IL-36α was detected in microparticles shed from AECs and promoted the production of pro-inflammatory cytokines and chemokines in respiratory cells. IL-36R-deficient mice were protected from influenza virus-induced lung injury and mortality. Decreased mortality was associated with significantly reduced early accumulation of neutrophils and monocytes/macrophages, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines, and permeability of the alveolar-epithelial barrier in despite impaired viral clearance. Taken together, these data indicate that IL-36 ligands exacerbate lung injury during influenza virus infection.

Original languageEnglish
Pages (from-to)1043-1055
Number of pages13
JournalMucosal Immunology
Volume10
Issue number4
DOIs
Publication statusPublished - 2017 Jul 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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