title: A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans.
abstract: Candida sp. are opportunistic fungal pathogens that colonize the skin and oral cavity and, when overgrown under permissive conditions, cause inflammation and disease. Previously, we identified a central role for the NLRP3 inflammasome in regulating IL-1β production and resistance to dissemination from oral infection with Candida albicans. Here we show that mucosal expression of NLRP3 and NLRC4 is induced by Candida infection, and up-regulation of these molecules is impaired in NLRP3 and NLRC4 deficient mice. Additionally, we reveal a role for the NLRC4 inflammasome in anti-fungal defenses. NLRC4 is important for control of mucosal Candida infection and impacts inflammatory cell recruitment to infected tissues, as well as protects against systemic dissemination of infection. Deficiency in either NLRC4 or NLRP3 results in severely attenuated pro-inflammatory and antimicrobial peptide responses in the oral cavity. Using bone marrow chimeric mouse models, we show that, in contrast to NLRP3 which limits the severity of infection when present in either the hematopoietic or stromal compartments, NLRC4 plays an important role in limiting mucosal candidiasis when functioning at the level of the mucosal stroma. Collectively, these studies reveal the tissue specific roles of the NLRP3 and NLRC4 inflammasome in innate immune responses against mucosal Candida infection.
authors.affiliation: Center for Global Health and Diseases, Case Western Reserve University, School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Tomalka
authors.forename: Sandhya
authors.initials: S
authors.lastname: Ganesan
authors.forename: Elaheh
authors.initials: E
authors.lastname: Azodi
authors.forename: Krupen
authors.initials: K
authors.lastname: Patel
authors.forename: Parth
authors.initials: P
authors.lastname: Majmudar
authors.forename: Brian A
authors.initials: BA
authors.lastname: Hall
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Amy G
authors.initials: AG
authors.lastname: Hise
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology* / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D002176:Candida albicans / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D007113:Immunity, Innate / Q000276:immunology*; D018928:Immunity, Mucosal; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009061:Mouth Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D058847:Inflammasomes; C512299:Ipaf protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse