Abstract
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 Paracoccidioides brasiliensis 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 in vivo studies, C57BL/6 mice deficient for several NLRP3 inflammasome components (Nlrp3−/−, Casp1/11−/−, Asc−/−) as well as deficient for ATP receptor (P2x7r−/−) were infected via i.t. with P. brasiliensis and several parameters of immunity and disease severity analyzed at the acute and chronic periods of infection. Pulmonary PCM was more severe in Nlrp3−/−, Casp1/11−/−, Asc−/−, and P2x7r−/− 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+ and CD8+ T cells. The decreased T cell immunity was concomitant with increased expansion of CD4+CD25+Foxp3 regulatory T (Treg) cells. Characterization of intracellular cytokines showed a persistent reduction of CD4+ and CD8+ 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.
Highlights
Paracoccidioides brasiliensis is the etiological agent of paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Latin America [1]
Using our murine model of resistance and susceptibility to PCM, it was verified that the activation of NOD-like receptor P3 (NLRP3) inflammasome by P. brasiliensis infection of macrophages from resistant A/J mice is dependent on dectin1-Syk signaling [21]
Other studies showed the role of TLR2, TLR4, dectin-1, and MyD88 signaling in the secretion of proinflammatory cytokines (IL-1β, TNF-α, and IL-6) and control of protective Th1/Th17 immune responses [5, 18, 20]
Summary
Paracoccidioides brasiliensis is the etiological agent of paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Latin America [1]. TLR2 and TLR4 sense P. brasiliensis mediated by MyD88-dependent signaling that leads to cytokines production by alveolar and peritoneal macrophages [6, 7, 17, 18] These components were seen to control the adaptive immunity and severity of disease developed by P. brasiliensis infected mice [6, 7, 18]. C-type lectin receptors (CLRs) like mannose receptor (MR) and dectin-1 as well as the complement receptors 3 play an important role in P. brasiliensis recognition and activation of immune cells [8, 19,20,21,22] These studies have demonstrated that in pulmonary PCM, as in other infectious pathologies, PRRs are key elements that govern protective immunity, which must be tightly controlled by antiinflammatory mechanisms as those mediated by Treg cells and their products [5,6,7]
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