AUTHOR=Albuquerque Jose Antonio Tavares de , Banerjee Pinaki Prosad , Castoldi Angela , Ma Royce , Zurro Nuria Bengala , Ynoue Leandro Hideki , Arslanian Christina , Barbosa-Carvalho Marina Uchoa Wall , Correia-Deur Joya Emilie de Menezes , Weiler Fernanda Guimarães , Dias-da-Silva Magnus Regios , Lazaretti-Castro Marise , Pedroza Luis Alberto , Câmara Niels Olsen Saraiva , Mace Emily , Orange Jordan Scott , Condino-Neto Antonio TITLE=The Role of AIRE in the Immunity Against Candida Albicans in a Model of Human Macrophages JOURNAL=Frontiers in Immunology VOLUME=9 YEAR=2018 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.00567 DOI=10.3389/fimmu.2018.00567 ISSN=1664-3224 ABSTRACT=

Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a primary immunodeficiency caused by mutations in the autoimmune regulator gene (AIRE). Patients with AIRE mutations are susceptible to Candida albicans infection and present with autoimmune disorders. We previously demonstrated that cytoplasmic AIRE regulates the Syk-dependent Dectin-1 pathway. In this study, we further evaluated direct contact with fungal elements, synapse formation, and the response of macrophage-like THP-1 cells to C. albicans hyphae to determine the role of AIRE upon Dectin receptors function and signaling. We examined the fungal synapse (FS) formation in wild-type and AIRE-knockdown THP-1 cells differentiated to macrophages, as well as monocyte-derived macrophages from APECED patients. We evaluated Dectin-2 receptor signaling, phagocytosis, and cytokine secretion upon hyphal stimulation. AIRE co-localized with Dectin-2 and Syk at the FS upon hyphal stimulation of macrophage-like THP-1 cells. AIRE-knockdown macrophage-like THP-1 cells exhibited less Dectin-1 and Dectin-2 receptors accumulation, decreased signaling pathway activity at the FS, lower C. albicans phagocytosis, and less lysosome formation. Furthermore, IL-1β, IL-6, or TNF-α secretion by AIRE-knockdown macrophage-like THP-1 cells and AIRE-deficient patient macrophages was decreased compared to control cells. Our results suggest that AIRE modulates the FS formation and hyphal recognition and help to orchestrate an effective immune response against C. albicans.