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

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-36α and IL-36γ mRNA and protein production in the lung. Compared to the findings for L. pneumophila-infected wild-type (WT) mice, the i.t. administration of L. pneumophila to IL-36 receptor-deficient (IL-36R-/-) 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-/- 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-/- mice compared to macrophages from WT mice. While L. pneumophila-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 L. pneumophila pneumonia.

• Authors: Yuta Nanjo, Michael W Newstead, Tetsuji Aoyagi, Xianying Zeng, Kazuhisa Takahashi, Fu Shin Yu, Kazuhiro Tateda, Theodore J Standiford
• Journal: Infection and immunity (Infect Immun) Vol. 87 Issue 1 (01 2019) ISSN: 1098-5522 [Electronic] United States
• PMID: 30323031 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 American Society for Microbiology.

Chemical References

• Interleukin-1
• interleukin-36, mouse

Topics

• Animals
• Disease Models, Animal
• Female
• Interleukin-1 (deficiency, metabolism)
• Legionella pneumophila (immunology)
• Legionnaires' Disease (immunology, pathology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Survival Analysis