Interleukin-36γ and IL-36 receptor signaling mediate impaired host immunity and lung injury in cytotoxic Pseudomonas aeruginosa pulmonary infection: Role of prostaglandin E2.
Interleukin-36γ and IL-36 receptor signaling mediate impaired host immunity and lung injury in cytotoxic Pseudomonas aeruginosa pulmonary infection: Role of prostaglandin E2.
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DOI：
10.1371/journal.ppat.1006737
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发表时间：
2017-11
期刊：
影响因子：
6.7
通讯作者：
Standiford TJ
中科院分区：
文献类型：
--
作者：
Aoyagi T;Newstead MW;Zeng X;Nanjo Y;Peters-Golden M;Kaku M;Standiford TJ
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. Pneumonia caused by Pseudomonas aeruginosa is a serious infection resulting in significant lung injury and mortality in susceptible hosts. The first line of defense in P. aeruginosa lung infection are neutrophils and macrophages, which play a pivotal role in the rapid clearance of pathogens from the lung. However, excessive innate responses against microbial pathogens can promote collateral damage to lung tissue, culminating in acute lung injury. Here, we demonstrated the role of IL-36 cytokines in modulating the innate immune response to P. aeruginosa pulmonary infection. The elaboration of interleukin (IL)-36γ in the alveolar space was observed not only in mice during P. aeruginosa pulmonary infection but also patients with pneumonia due to P. aeruginosa. 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. Taken together, blockage of IL-36γ and its receptor signal may represent a viable immunomodulatory therapeutic approach in cytotoxic pseudomonas respiratory infection.
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DOI：
10.4049/jimmunol.1003162
发表时间：
2011-02-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Johnston A;Xing X;Guzman AM;Riblett M;Loyd CM;Ward NL;Wohn C;Prens EP;Wang F;Maier LE;Kang S;Voorhees JJ;Elder JT;Gudjonsson JE
通讯作者：
Gudjonsson JE
DOI：
10.4049/jimmunol.0902828
发表时间：
2010-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Hubbard LL;Ballinger MN;Thomas PE;Wilke CA;Standiford TJ;Kobayashi KS;Flavell RA;Moore BB
通讯作者：
Moore BB
影响因子：
3.1
作者：
Laichalk, LL;Kunkel, SL;Standiford, TJ
通讯作者：
Standiford, TJ
影响因子：
20.3
作者：
Chizzolini, Carlo;Chicheportiche, Rachel;Dayer, Jean-Michel
通讯作者：
Dayer, Jean-Michel
影响因子：
9.3
作者：
Bozoyan L;Dumas A;Patenaude A;Vallières L
通讯作者：
Vallières L