Department of Medicine, Division of Infectious Diseases and Immunology
Animals; Apoptosis Regulatory Proteins; Calcium-Binding Proteins; Candida albicans; Candidiasis; Carrier Proteins; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Immunity, Innate; Immunity, Mucosal; Inflammasomes; Mice; Mice, Inbred C57BL; Mice, Knockout; Mouth Mucosa; Real-Time Polymerase Chain Reaction
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-1beta 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.
Tomalka, Jeffrey; Ganesan, Sandhya; Azodi, Elaheh; Patel, Krupen; Majmudar, Parth; Hall, Brian A.; Fitzgerald, Katherine A.; and Hise, Amy G., "A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans" (2011). Infectious Diseases and Immunology Publications and Presentations. 135.