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

Interleukin-36 gamma (IL-36 gamma) 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-36 gamma deficiency to assess the contribution of IL-36 gamma in the lung during experimental pneumonia. Induction of IL-36 gamma was observed in the lung in response to Streptococcus pneumoniae (Sp) infection, and mature IL-36 gamma protein was secreted primarily in microparticles. IL-36 gamma-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-36 gamma directly stimulated type-1 cytokine induction from dendritic cells in vitro in a MyD88-dependent manner. Similar protective effects of IL-36 gamma were observed in a Gram-negative pneumonia model (Klebsiella pneumoniae). Intrapulmonary delivery of IL-36 gamma-containing microparticles reconstituted immunity in IL-36 gamma(-/-) mice. Enhanced expression of IL-36 gamma was also observed in plasma and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome because of pneumonia. These studies indicate that IL-36 gamma assumes a vital proximal role in the lung innate mucosal immunity during bacterial pneumonia by driving protective type-1 responses and classical macrophage activation.