Interleukin-36γ and IL-36 receptor signaling mediate impaired host immunity and lung injury in cytotoxic Pseudomonas aeruginosa pulmonary infection: Role of prostaglandin E2

Tetsuji Aoyagi,Marc Peters-Golden,Michael W Newstead,Theodore J Standiford,Xianying Zeng,Yuta Nanjo,Mitsuo Kaku,Dario S Zamboni

doi:10.1371/journal.ppat.1006737

Tetsuji Aoyagi, Marc Peters-Golden + Show 6 more

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https://doi.org/10.1371/journal.ppat.1006737

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Abstract

Pseudomonas aeruginosa is a Gram-negative pathogen that can lead to severe infection associated with lung injury and high mortality. The interleukin (IL)-36 cytokines (IL-36α, IL-36β and IL-36γ) are newly described IL-1 like family cytokines that promote inflammatory response via binding to the IL-36 receptor (IL-36R). Here we investigated the functional role of IL-36 cytokines in the modulating of innate immune response against P. aeruginosa pulmonary infection. The intratracheal administration of flagellated cytotoxic P. aeruginosa (ATCC 19660) upregulated IL-36α and IL-36γ, but not IL-36β, in the lungs. IL-36α and IL-36γ were expressed in pulmonary macrophages (PMs) and alveolar epithelial cells in response to P. aeruginosa in vitro. Mortality after bacterial challenge in IL-36 receptor deficient (IL-36R-/-) mice and IL-36γ deficient (IL-36γ-/-) mice, but not IL-36α deficient mice, was significantly lower than that of wild type mice. Decreased mortality in IL-36R-/- mice and IL-36γ-/- mice was associated with reduction in bacterial burden in the alveolar space, bacterial dissemination, production of inflammatory cytokines and lung injury, without changes in lung leukocyte influx. Interestingly, IL-36γ enhanced the production of prostaglandin E2 (PGE2) during P. aeruginosa infection in vivo and in vitro. Treatment of PMs with recombinant IL-36γ resulted in impaired bacterial killing via PGE2 and its receptor; EP2. P. aeruginosa infected EP2 deficient mice or WT mice treated with a COX-2-specific inhibitor showed decreased bacterial burden and dissemination, but no change in lung injury. Finally, we observed an increase in IL-36γ, but not IL-36α, in the airspace and plasma of patients with P. aeruginosa-induced acute respiratory distress syndrome. Thus, IL-36γ and its receptor signal not only impaired bacterial clearance in a possible PGE2 dependent fashion but also mediated lung injury during P. aeruginosa infection.

Highlights

Pseudomonas aeruginosa is a Gram-negative bacterium that causes acute nosocomial infection as well as chronic infection in immunocompromised hosts
We demonstrated the role of IL-36 cytokines in modulating the innate immune response to P. aeruginosa pulmonary infection
In murine P. aeruginosa lung infection, deletion of IL-36γ or its receptor resulted in improved bacterial clearance associated with reduced prostaglandin E2 production, and attenuated lung injury independent of changes in leukocyte influx

Summary

Introduction

Pseudomonas aeruginosa is a Gram-negative bacterium that causes acute nosocomial infection as well as chronic infection in immunocompromised hosts. The IL-36 receptor ligands induce pro-inflammatory cytokine and chemokine expression and contribute to neutrophil accumulation, dendritic cell activation and polarization of T helper 1 and IL-17 producing T cells [4, 8, 9]. Innate immune cell recruitment and phagocytic bacterial clearance, including neutrophils and macrophages, have critical roles in the host defense during the early stage of P. aeruginosa infection [12, 13]. IL-36γ mRNA is upregulated in human bronchial cells after infection with P. aeruginosa [14] Taken together, these observations suggest that IL-36 cytokines may play an important role in host defense against P. aeruginosa, perhaps by contributing to inflammatory cell recruitment/activation during infection, To date, the role of IL-36 cytokines in the host defense of P. aeruginosa infection has not been defined

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