title: Chitinase 3-Like 1 (Chil1) Regulates Survival and Macrophage-Mediated Interleukin-1β and Tumor Necrosis Factor Alpha during Pseudomonas aeruginosa Pneumonia.
abstract: 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-1β (IL-1β) production, and host tissue damage. Chitinase 3-like-1 (Chil1) is expressed during infection and binds to its receptor, IL-13 receptor α2 (IL-13Rα2), 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-α) and IL-1β 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-1β production compared to BMDMs from WT mice. The addition of recombinant Chil1 decreases the excessive IL-1β production but only partially rescues stimulated BMDMs from IL-13Rα2-deficient mice. Our data provide mechanistic insights into how Chil1 regulates P. aeruginosa-induced host responses.
authors.affiliation: 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.
authors.forename: Chad R
authors.initials: CR
authors.lastname: Marion
authors.affiliation: Yale University School of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, New Haven, Connecticut, USA.
authors.forename: Jianmiao
authors.initials: J
authors.lastname: Wang
authors.affiliation: Yale University School of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, New Haven, Connecticut, USA.
authors.forename: Lokesh
authors.initials: L
authors.lastname: Sharma
authors.affiliation: Yale University School of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, New Haven, Connecticut, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Losier
authors.affiliation: Yale University School of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, New Haven, Connecticut, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Lui
authors.affiliation: Yale University School of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, New Haven, Connecticut, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Andrews
authors.affiliation: Warren Alpert School of Medicine, Brown University, Providence, Rhode Island, USA.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
authors.affiliation: Yale University School of Medicine, Section of Infectious Diseases, New Haven, Connecticut, USA.|Yale University School of Medicine, Section of Microbial Pathogenesis, New Haven, Connecticut, USA.
authors.forename: Barbara I
authors.initials: BI
authors.lastname: Kazmierczak
authors.affiliation: Yale University School of Medicine, Section of Microbial Pathogenesis, New Haven, Connecticut, USA.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Roy
authors.affiliation: 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.|Yale University School of Medicine, Section of Microbial Pathogenesis, New Haven, Connecticut, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Dela Cruz
mesh_terms: D000818:Animals; D058491:Bacterial Load; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D000071451:Chitinase-3-Like Protein 1 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology* / Q000401:mortality; D011379:Prognosis; D011552:Pseudomonas Infections / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology* / Q000401:mortality; D011550:Pseudomonas aeruginosa; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000071451:Chitinase-3-Like Protein 1; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha