AUTHOR=Feriotti Claudia , de Araújo Eliseu Frank , Loures Flavio Vieira , da Costa Tania Alves , Galdino Nayane Alves de Lima , Zamboni Dario Simões , Calich Vera Lucia Garcia 

TITLE=NOD-Like Receptor P3 Inflammasome Controls Protective Th1/Th17 Immunity against Pulmonary Paracoccidioidomycosis

JOURNAL=Frontiers in Immunology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00786

DOI=10.3389/fimmu.2017.00786

ISSN=1664-3224

ABSTRACT=<p>The NOD-like receptor P3 (NLRP3) inflammasome is an intracellular multimeric complex that triggers the activation of inflammatory caspases and the maturation of IL-1β and IL-18, important cytokines for the innate immune response against pathogens. The functional NLRP3 inflammasome complex consists of NLRP3, the adaptor protein apoptosis-associated speck-like protein, and caspase-1. Various molecular mechanisms were associated with NLRP3 activation including the presence of extracellular ATP, recognized by the cell surface P2X7 receptor (P2X7R). Several pattern recognition receptors on innate immune cells recognize <italic>Paracoccidioides brasiliensis</italic> components resulting in diverse responses that influence adaptive immunity and disease outcome. However, the role of NLRP3 inflammasome was scantily investigated in pulmonary paracoccidioidomycosis (PCM), leading us to use an intratracheal (i.t.) model of infection to study the influence of this receptor in anti-fungal immunity and severity of infection. For <italic>in vivo</italic> studies, <italic>C57BL/6</italic> mice deficient for several NLRP3 inflammasome components (<italic>Nlrp3</italic><sup>−/−</sup>, <italic>Casp1/11</italic><sup>−/−</sup>, <italic>Asc</italic><sup>−/−</sup>) as well as deficient for ATP receptor (<italic>P2x7r</italic><sup>−/−</sup>) were infected <italic>via</italic> i.t. with <italic>P. brasiliensis</italic> and several parameters of immunity and disease severity analyzed at the acute and chronic periods of infection. Pulmonary PCM was more severe in <italic>Nlrp3</italic><sup>−/−</sup>, <italic>Casp1/11</italic><sup>−/−</sup>, <italic>Asc</italic><sup>−/−</sup>, and <italic>P2x7r</italic><sup>−/−</sup> mice as demonstrated by the increased fungal burdens, mortality rates and tissue pathology developed. The more severe disease developed by NLRP3, ASC, and Caspase-1/11 deficient mice was associated with decreased production of IL-1β and IL-18 and reduced inflammatory reactions mediated by PMN leukocytes and activated CD4<sup>+</sup> and CD8<sup>+</sup> T cells. The decreased T cell immunity was concomitant with increased expansion of CD4<sup>+</sup>CD25<sup>+</sup>Foxp3 regulatory T (Treg) cells. Characterization of intracellular cytokines showed a persistent reduction of CD4<sup>+</sup> and CD8<sup>+</sup> T cells expressing IFN-γ and IL-17 whereas those producing IL-4 and TGF-β appeared in increased frequencies. Histopathological studies showed that all deficient mouse strains developed more severe lesions containing elevated numbers of budding yeast cells resulting in increased mortality rates. Altogether, these findings led us to conclude that the activation of the NLRP3 inflammasome has a crucial role in the immunoprotection against pulmonary PCM by promoting the expansion of Th1/Th17 immunity and reducing the suppressive control mediated by Treg cells.</p>