PMID- 29166668 OWN - NLM STAT- MEDLINE DCOM- 20171214 LR - 20201214 IS - 1553-7374 (Electronic) IS - 1553-7366 (Print) IS - 1553-7366 (Linking) VI - 13 IP - 11 DP - 2017 Nov TI - Interleukin-36gamma and IL-36 receptor signaling mediate impaired host immunity and lung injury in cytotoxic Pseudomonas aeruginosa pulmonary infection: Role of prostaglandin E2. PG - e1006737 LID - 10.1371/journal.ppat.1006737 [doi] LID - e1006737 AB - 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-36alpha, IL-36beta and IL-36gamma) 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-36alpha and IL-36gamma, but not IL-36beta, in the lungs. IL-36alpha and IL-36gamma 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-36gamma deficient (IL-36gamma-/-) mice, but not IL-36alpha deficient mice, was significantly lower than that of wild type mice. Decreased mortality in IL-36R-/- mice and IL-36gamma-/- 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-36gamma enhanced the production of prostaglandin E2 (PGE2) during P. aeruginosa infection in vivo and in vitro. Treatment of PMs with recombinant IL-36gamma 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-36gamma, but not IL-36alpha, in the airspace and plasma of patients with P. aeruginosa-induced acute respiratory distress syndrome. Thus, IL-36gamma and its receptor signal not only impaired bacterial clearance in a possible PGE2 dependent fashion but also mediated lung injury during P. aeruginosa infection. FAU - Aoyagi, Tetsuji AU - Aoyagi T AUID- ORCID: 0000-0001-6821-9701 AD - Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America. AD - Department of Infection Control and Laboratory Diagnostics, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. FAU - Newstead, Michael W AU - Newstead MW AD - Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America. FAU - Zeng, Xianying AU - Zeng X AD - Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America. FAU - Nanjo, Yuta AU - Nanjo Y AD - Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America. AD - Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan. FAU - Peters-Golden, Marc AU - Peters-Golden M AUID- ORCID: 0000-0002-9768-0262 AD - Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America. FAU - Kaku, Mitsuo AU - Kaku M AD - Department of Infection Control and Laboratory Diagnostics, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. FAU - Standiford, Theodore J AU - Standiford TJ AUID- ORCID: 0000-0002-5890-4470 AD - Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America. LA - eng GR - P50 HL074024/HL/NHLBI NIH HHS/United States GR - R01 HL097564/HL/NHLBI NIH HHS/United States GR - R01 HL123515/HL/NHLBI NIH HHS/United States PT - Journal Article DEP - 20171122 PL - United States TA - PLoS Pathog JT - PLoS pathogens JID - 101238921 RN - 0 (Cytokines) RN - 0 (Interleukin-1) RN - 0 (Receptors, Interleukin-1) RN - 0 (interleukin-36 receptor, mouse) RN - 0 (interleukin-36, mouse) RN - K7Q1JQR04M (Dinoprostone) SB - IM MH - Animals MH - Cytokines/metabolism MH - Dinoprostone/*metabolism MH - Immunity, Innate/*immunology MH - Interleukin-1/genetics/*metabolism MH - Lung Injury/*metabolism MH - Macrophages, Alveolar/immunology MH - Mice, Knockout MH - Pseudomonas Infections/*immunology/metabolism MH - Pseudomonas aeruginosa MH - Receptors, Interleukin-1/genetics/*metabolism MH - *Signal Transduction/immunology PMC - PMC5718565 COIS- The authors have declared that no competing interests exist. EDAT- 2017/11/23 06:00 MHDA- 2017/12/15 06:00 PMCR- 2017/11/22 CRDT- 2017/11/23 06:00 PHST- 2017/03/04 00:00 [received] PHST- 2017/11/07 00:00 [accepted] PHST- 2017/12/06 00:00 [revised] PHST- 2017/11/23 06:00 [pubmed] PHST- 2017/12/15 06:00 [medline] PHST- 2017/11/23 06:00 [entrez] PHST- 2017/11/22 00:00 [pmc-release] AID - PPATHOGENS-D-17-00414 [pii] AID - 10.1371/journal.ppat.1006737 [doi] PST - epublish SO - PLoS Pathog. 2017 Nov 22;13(11):e1006737. doi: 10.1371/journal.ppat.1006737. eCollection 2017 Nov.