title: NLRC4 inflammasome-mediated production of IL-1β modulates mucosal immunity in the lung against gram-negative bacterial infection.
abstract: Bacterial flagellin is critical to mediate NLRC4 inflammasome-dependent caspase-1 activation. However, Shigella flexneri, a nonflagellated bacterium, and a flagellin (fliC) knockout strain of Pseudomonas aeruginosa are known to activate NLRC4 in bone marrow-derived macrophages. Furthermore, the flagellin-deficient fliC strain of P. aeruginosa was used in a mouse model of peritonitis to show the requirement of NLRC4. In a model of pulmonary P. aeruginosa infection, flagellin was shown to be essential for the induction of NLRC4-dependent caspase-1 activation. Moreover, in all P. aeruginosa studies, IL-1β production was attenuated in NLRC4(-/-) mice; however, the role of IL-1β in NLRC4-mediated innate immunity in the lungs against a nonflagellated bacterium was not explored. In this article, we report that NLRC4 is important for host survival and bacterial clearance, as well as neutrophil-mediated inflammation in the lungs following Klebsiella pneumoniae infection. NLRC4 is essential for K. pneumoniae-induced production of IL-1β, IL-17A, and neutrophil chemoattractants (keratinocyte cell-derived chemokines, MIP-2, and LPS-induced CXC chemokines) in the lungs. NLRC4 signaling in hematopoietic cells contributes to K. pneumoniae-induced lung inflammation. Furthermore, exogenous IL-1β, but not IL-18 or IL-17A, partially rescued survival, neutrophil accumulation, and cytokine/chemokine expression in the lungs of NLRC4(-/-) mice following infectious challenge. Furthermore, IL-1R1(-/-) mice displayed a decrease in neutrophilic inflammation in the lungs postinfection. Taken together, these findings provide novel insights into the role of NLRC4 in host defense against K. pneumoniae infection.
authors.affiliation: Laboratory of Lung Biology, Department of Pathobiological Sciences, Center for Experimental Infectious Disease Research, Louisiana State University, Baton Rouge, LA 70803, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Cai
authors.forename: Sanjay
authors.initials: S
authors.lastname: Batra
authors.forename: Nobuko
authors.initials: N
authors.lastname: Wakamatsu
authors.forename: Pal
authors.initials: P
authors.lastname: Pacher
authors.forename: Samithamby
authors.initials: S
authors.lastname: Jeyaseelan
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D020170:Caspase 1 / Q000378:metabolism; D005260:Female; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology; D058847:Inflammasomes / Q000172:deficiency / Q000502:physiology*; D018836:Inflammation Mediators / Q000502:physiology; D053583:Interleukin-1beta / Q000096:biosynthesis*; D007710:Klebsiella Infections / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D012141:Respiratory Tract Infections / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; D018836:Inflammation Mediators; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D020170:Caspase 1