title: Galectin-3 functions as an alarmin: pathogenic role for sepsis development in murine respiratory tularemia.
abstract: Sepsis is a complex immune disorder with a mortality rate of 20-50% and currently has no therapeutic interventions. It is thus critical to identify and characterize molecules/factors responsible for its development. We have recently shown that pulmonary infection with Francisella results in sepsis development. As extensive cell death is a prominent feature of sepsis, we hypothesized that host endogenous molecules called alarmins released from dead or dying host cells cause a hyperinflammatory response culminating in sepsis development. In the current study we investigated the role of galectin-3, a mammalian β-galactoside binding lectin, as an alarmin in sepsis development during F. novicida infection. We observed an upregulated expression and extracellular release of galectin-3 in the lungs of mice undergoing lethal pulmonary infection with virulent strain of F. novicida but not in those infected with a non-lethal, attenuated strain of the bacteria. In comparison with their wild-type C57Bl/6 counterparts, F. novicida infected galectin-3 deficient (galectin-3(-/-)) mice demonstrated significantly reduced leukocyte infiltration, particularly neutrophils in their lungs. They also exhibited a marked decrease in inflammatory cytokines, vascular injury markers, and neutrophil-associated inflammatory mediators. Concomitantly, in-vitro pre-treatment of primary neutrophils and macrophages with recombinant galectin-3 augmented F. novicida-induced activation of these cells. Correlating with the reduced inflammatory response, F. novicida infected galectin-3(-/-) mice exhibited improved lung architecture with reduced cell death and improved survival over wild-type mice, despite similar bacterial burden. Collectively, these findings suggest that galectin-3 functions as an alarmin by augmenting the inflammatory response in sepsis development during pulmonary F. novicida infection.
authors.affiliation: Department of Microbiology and Immunology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, United States of America.
authors.forename: Bibhuti B
authors.initials: BB
authors.lastname: Mishra
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Steichen
authors.forename: Brandilyn J
authors.initials: BJ
authors.lastname: Binstock
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Metzger
authors.forename: Judy M
authors.initials: JM
authors.lastname: Teale
authors.forename: Jyotika
authors.initials: J
authors.lastname: Sharma
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D016207:Cytokines / Q000276:immunology; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D037502:Galectin 3 / Q000235:genetics / Q000276:immunology*; D007155:Immunologic Factors / Q000276:immunology*; D020287:In Situ Nick-End Labeling; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D012141:Respiratory Tract Infections / Q000150:complications* / Q000382:microbiology / Q000503:physiopathology; D018805:Sepsis / Q000209:etiology* / Q000276:immunology* / Q000378:metabolism; D014406:Tularemia / Q000150:complications* / Q000503:physiopathology
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D017931:DNA Primers; D037502:Galectin 3; D007155:Immunologic Factors