Overlapping Roles for Interleukin-36 Cytokines in Protective Host Defense against MurineLegionella pneumophilaPneumonia

Abstract

Legionella pneumophila causes life-threatening pneumonia culminating in acute lung injury. Innate and adaptive cytokines play an important role in host defense against L. pneumophila 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 L. pneumophila. Intratracheal (i.t.) administration of L. pneumophila induced the upregulation of both IL-36␣ and IL-36␥ mRNA and protein production in the lung. Compared to the findings for L. pneumophila-infected wildtype (WT) mice, the i.t. administration of L. pneumophila to IL-36 receptor-deficient (IL-36R Ϫ/Ϫ ) mice resulted in increased mortality, a delay in lung bacterial clearance, increased L. pneumophila dissemination to extrapulmonary organs, and impaired glucose homeostasis. Impaired lung bacterial clearance in IL-36R Ϫ/Ϫ mice was associated with a significantly reduced accumulation of inflammatory cells and the decreased production of proinflammatory cytokines and chemokines. Ex vivo, reduced expression of costimulatory molecules and impaired M1 polarization were observed in alveolar macrophages isolated from infected IL-36R Ϫ/Ϫ mice compared to macrophages from WT mice. While L. pneumophila-induced mortality in IL-36␣-or IL-36␥deficient mice was not different from that in WT animals, antibody-mediated neutralization of IL-36␥ in IL-36␣ Ϫ/Ϫ mice resulted in mortality similar to that observed in IL-36R Ϫ/Ϫ mice, indicating redundant and overlapping roles for these cytokines in experimental murine L. pneumophila pneumonia.

IL-36α Exerts Proinflammatory Effects in Aspergillus fumigatus Keratitis of Mice Through the Pathway of IL-36α/IL-36R/NF-κB

“…These data, suggesting that IL-36α plays a potential role in the development of A. fumigatus keratitis, are consistent with results in a previous study from another laboratory indicating that IL-36α was induced after infection and correlated with the development of Legionella pneumophila pneumonia. 17 This was further confirmed by an in vitro study that reported that the expression of IL-36α was significantly increased in the primary macrophages stimulated with A. fumigatus hyphae.…”

Thrombospondin-1 Restricts Interleukin-36γ-Mediated Neutrophilic Inflammation during Pseudomonas aeruginosa Pulmonary Infection

“…IL-36 cytokines are major effectors of the immune response in the lungs during P. aeruginosa and other bacterial infections ( 30 , 31 , 34 ). Il36a transcript level was increased in the lungs by 1 dpi ( Fig.…”

“…Neutralizing anti-IL-36γ antibody was generated in New Zealand White rabbits that were immunized with recombinant mouse IL-36γ ( 30 , 34 ). The antibody was purified and measured for titer by ELISA ( 30 , 34 ).…”

“…IL-36 cytokines bind to a common IL-36 receptor (IL-1Rrp2), triggering the recruitment of the IL1RAcP accessory protein and leading to signal transduction through MyD88 and downstream MAPK and NF-κB activation ( 32 , 33 ). IL-36γ appears to be protective during lung infection caused by different pathogenic bacteria such as Streptococcus pneumoniae , Klebsiella pneumoniae , and Legionella pneumophila ( 30 , 34 ). In contrast to these infections, IL-36γ is paradoxically harmful following P. aeruginosa infection-induced injury, as IL-36R-deficient (IL-36R −/− ) and IL-36γ −/− mice are protected from excessive host inflammatory response and show improved lung bacterial clearance ( 31 ).…”

New Insights in Candida albicans Innate Immunity at the Mucosa: Toxins, Epithelium, Metabolism, and Beyond

“…Additionally, IL-36 has been shown to be important in a number of infections at different mucosal sites. At these surfaces, it induces a series of different AMPs and other protective factors, including peptidoglycan recognition protein 2, human β-defensin 2, or matrix metallopeptidase 9 (Huynh et al, 2016;Aoyagi et al, 2017;Kovach et al, 2017;Nanjo et al, 2018;Scholz et al, 2018;Heath et al, 2019).…”