Overlapping Roles for Interleukin-36 Cytokines in Protective Host Defense against Murine Legionella pneumophila Pneumonia

causes life-threatening pneumonia culminating in acute lung injury. Innate and adaptive cytokines play an important role in host defense against infection. Interleukin-36 (IL-36) cytokines are recently described members of the larger IL-1 cytokine family known to exert potent inflammatory effects. In this study, we elucidated the role for IL-36 cytokines in experimental pneumonia caused by Intratracheal (i.t.) administration of induced the upregulation of both IL-36α and IL-36γ mRNA and protein production in the lung. Compared to the findings for -infected wild-type (WT) mice, the i.t. administration of to IL-36 receptor-deficient (IL-36R ) mice resulted in increased mortality, a delay in lung bacterial clearance, increased dissemination to extrapulmonary organs, and impaired glucose homeostasis. Impaired lung bacterial clearance in IL-36R mice was associated with a significantly reduced accumulation of inflammatory cells and the decreased production of proinflammatory cytokines and chemokines. , reduced expression of costimulatory molecules and impaired M1 polarization were observed in alveolar macrophages isolated from infected IL-36R mice compared to macrophages from WT mice. While -induced mortality in IL-36α- or IL-36γ-deficient mice was not different from that in WT animals, antibody-mediated neutralization of IL-36γ in IL-36α mice resulted in mortality similar to that observed in IL-36R mice, indicating redundant and overlapping roles for these cytokines in experimental murine pneumonia.