PMID- 27141083 OWN - NLM STAT- MEDLINE DCOM- 20170518 LR - 20201209 IS - 1098-5522 (Electronic) IS - 0019-9567 (Print) IS - 0019-9567 (Linking) VI - 84 IP - 7 DP - 2016 Jul TI - Chitinase 3-Like 1 (Chil1) Regulates Survival and Macrophage-Mediated Interleukin-1beta and Tumor Necrosis Factor Alpha during Pseudomonas aeruginosa Pneumonia. PG - 2094-2104 LID - 10.1128/IAI.00055-16 [doi] AB - Pseudomonas aeruginosa causes hospital-acquired pneumonia and is associated with high mortality. An effective response to such an infection includes efficient clearance of pathogenic organisms while limiting collateral damage from the host inflammatory response, known as host resistance and host tolerance, respectively. P. aeruginosa expresses a type III secretion system (T3SS) needle complex that induces NLRC4 (NOD-like receptor C4) activation, interleukin-1beta (IL-1beta) production, and host tissue damage. Chitinase 3-like-1 (Chil1) is expressed during infection and binds to its receptor, IL-13 receptor alpha2 (IL-13Ralpha2), to regulate the pathogen-host response during Streptococcus pneumoniae infection, but the role Chil1 plays in balancing the host resistance and host tolerance during P. aeruginosa pneumonia is not known. We conducted experiments using C57BL/6 mice with or without a genetic deficiency of Chil1 and demonstrated that Chil1-deficient mice succumb to P. aeruginosa infection more rapidly than the wild type (WT). The decreased survival time in infected Chil1-deficient mice is associated with more neutrophils recruited to the airways, more lung parenchymal damage, and increased pulmonary consolidation while maintaining equivalent bacterial killing compared to WT mice. Infected Chil1-deficient mice and bone marrow-derived macrophages (BMDMs) from Chil1-deficient mice have increased production of tumor necrosis factor alpha (TNF-alpha) and IL-1beta compared to infected WT mice and macrophages. Infection of Chil1-deficient BMDMs with non-NLRC4-triggering P. aeruginosa, which is deficient in the T3SS needle complex, did not alter the excessive IL-1beta production compared to BMDMs from WT mice. The addition of recombinant Chil1 decreases the excessive IL-1beta production but only partially rescues stimulated BMDMs from IL-13Ralpha2-deficient mice. Our data provide mechanistic insights into how Chil1 regulates P. aeruginosa-induced host responses. CI - Copyright (c) 2016, American Society for Microbiology. All Rights Reserved. FAU - Marion, Chad R AU - Marion CR AD - Yale University School of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, New Haven, Connecticut, USA chad.marion@yale.edu charles.delacruz@yale.edu. FAU - Wang, Jianmiao AU - Wang J AD - Yale University School of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, New Haven, Connecticut, USA. FAU - Sharma, Lokesh AU - Sharma L AD - Yale University School of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, New Haven, Connecticut, USA. FAU - Losier, Ashley AU - Losier A AD - Yale University School of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, New Haven, Connecticut, USA. FAU - Lui, Wei AU - Lui W AD - Yale University School of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, New Haven, Connecticut, USA. FAU - Andrews, Nathaniel AU - Andrews N AD - Yale University School of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, New Haven, Connecticut, USA. FAU - Elias, Jack A AU - Elias JA AD - Warren Alpert School of Medicine, Brown University, Providence, Rhode Island, USA. FAU - Kazmierczak, Barbara I AU - Kazmierczak BI AD - Yale University School of Medicine, Section of Infectious Diseases, New Haven, Connecticut, USA. AD - Yale University School of Medicine, Section of Microbial Pathogenesis, New Haven, Connecticut, USA. FAU - Roy, Craig R AU - Roy CR AD - Yale University School of Medicine, Section of Microbial Pathogenesis, New Haven, Connecticut, USA. FAU - Dela Cruz, Charles S AU - Dela Cruz CS AD - Yale University School of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, New Haven, Connecticut, USA chad.marion@yale.edu charles.delacruz@yale.edu. AD - Yale University School of Medicine, Section of Microbial Pathogenesis, New Haven, Connecticut, USA. LA - eng GR - K08 HL103770/HL/NHLBI NIH HHS/United States GR - R01 AI048770/AI/NIAID NIH HHS/United States GR - UL1 TR001863/TR/NCATS NIH HHS/United States GR - T32 HL007778/HL/NHLBI NIH HHS/United States GR - UL1 TR000142/TR/NCATS NIH HHS/United States GR - R01 AI041699/AI/NIAID NIH HHS/United States GR - R01 HL126094/HL/NHLBI NIH HHS/United States PT - Journal Article DEP - 20160623 PL - United States TA - Infect Immun JT - Infection and immunity JID - 0246127 RN - 0 (Chitinase-3-Like Protein 1) RN - 0 (Interleukin-1beta) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Animals MH - Bacterial Load MH - Cell Death/genetics/immunology MH - Chemotaxis, Leukocyte/genetics/immunology MH - Chitinase-3-Like Protein 1/genetics/*metabolism MH - Disease Models, Animal MH - Gene Expression MH - Interleukin-1beta/metabolism MH - Macrophages/*metabolism MH - Mice MH - Mice, Knockout MH - Pneumonia, Bacterial/immunology/*metabolism/*microbiology/mortality MH - Prognosis MH - Pseudomonas Infections/immunology/*metabolism/*microbiology/mortality MH - *Pseudomonas aeruginosa MH - Tumor Necrosis Factor-alpha/metabolism PMC - PMC4936356 EDAT- 2016/05/04 06:00 MHDA- 2017/05/19 06:00 PMCR- 2016/12/23 CRDT- 2016/05/04 06:00 PHST- 2016/01/31 00:00 [received] PHST- 2016/04/27 00:00 [accepted] PHST- 2016/05/04 06:00 [entrez] PHST- 2016/05/04 06:00 [pubmed] PHST- 2017/05/19 06:00 [medline] PHST- 2016/12/23 00:00 [pmc-release] AID - IAI.00055-16 [pii] AID - 00055-16 [pii] AID - 10.1128/IAI.00055-16 [doi] PST - epublish SO - Infect Immun. 2016 Jun 23;84(7):2094-2104. doi: 10.1128/IAI.00055-16. Print 2016 Jul.