Journal
MUCOSAL IMMUNOLOGY
Volume 10, Issue 4, Pages 1043-1055Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mi.2016.107
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Funding
- Tohoku University Leading Young Researcher Overseas Visit Program
- Japanese Society for the Promotion of Science [25860825]
- National Institutes of Health/National Heart Lung, and Blood Institute [NIH/NHLBI R01 HL123515, R01 HL097564]
- Grants-in-Aid for Scientific Research [25860825] Funding Source: KAKEN
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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-36 alpha mRNA and protein production in the lungs. In vitro, influenza virus-mediated IL-36 alpha but not IL-36 gamma is induced and secreted from alveolar epithelial cells (AECs) through both a caspase-1 and caspase-3/7 dependent pathway. IL-36 alpha 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.
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