IL-36γ is a crucial proximal component of protective type-1-mediated lung mucosal immunity in Gram-positive and -negative bacterial pneumonia

  • Mucosal Immunol. 2017 Sep;10(5):1320-1334. doi: 10.1038/mi.2016.130.
M A Kovach  1  2 ,  B Singer  1 ,  G Martinez-Colon  3 ,  M W Newstead  1 ,  X Zeng  1 ,  P Mancuso  4 ,  T A Moore  1 ,  S L Kunkel  5 ,  M Peters-Golden  1 ,  B B Moore  1  3 ,  T J Standiford  1
Affiliations
  • 1. Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
  • 2. Unit for Lung and Airway Research, Physiology Division, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • 3. Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
  • 4. Department of Nutritional Sciences and School of Public Health, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
  • 5. Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
PMID: 28176791 DOI: 10.1038/mi.2016.130
Abstract

Interleukin-36γ (IL-36γ) is a member of novel IL-1-like proinflammatory cytokine family that are highly expressed in epithelial tissues and several myeloid-derived cell types. Little is known about the role of the IL-36 family in mucosal immunity, including lung anti-bacterial responses. We used murine models of IL-36γ deficiency to assess the contribution of IL-36γ in the lung during experimental Pneumonia. Induction of IL-36γ was observed in the lung in response to Streptococcus pneumoniae (Sp) Infection, and mature IL-36γ protein was secreted primarily in microparticles. IL-36γ-deficient mice challenged with Sp demonstrated increased mortality, decreased lung Bacterial clearance and increased Bacterial dissemination, in association with reduced local expression of type-1 cytokines, and impaired lung macrophage M1 polarization. IL-36γ directly stimulated type-1 cytokine induction from dendritic cells in vitro in a MyD88-dependent manner. Similar protective effects of IL-36γ were observed in a Gram-negative Pneumonia model (Klebsiella pneumoniae). Intrapulmonary delivery of IL-36γ-containing microparticles reconstituted immunity in IL-36γ-/- mice. Enhanced expression of IL-36γ was also observed in plasma and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome because of Pneumonia. These studies indicate that IL-36γ assumes a vital proximal role in the lung innate mucosal immunity during Bacterial pneumonia by driving protective type-1 responses and classical macrophage activation.

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