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

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. © 2017 aoyagi et al.