Ketelut-Carneiro Natália, Silva Grace Kelly, Rocha Fernanda Agostini, Milanezi Cristiane Maria, Cavalcanti-Neto Florêncio Figueiredo, Zamboni Dario Simões, Silva João Santana
Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, São Paulo, Brazil;
Department of Pathology, University of Brasília, 70910-900 Brasília, Federal District, Brazil; and.
J Immunol. 2015 May 1;194(9):4507-17. doi: 10.4049/jimmunol.1402321. Epub 2015 Mar 30.
Pathogens are sensed by innate immune receptors that initiate an efficient adaptive immune response upon activation. The elements of the innate immune recognition process for Paracoccidioides brasiliensis include TLR-2, TLR-4, and dectin-1. However, there are additional receptors necessary for the host immune responses to P. brasiliensis. The nucleotide-binding oligomerization domain-like receptor (NLRs), which activate inflammasomes, are candidate receptors that deserve renewed investigation. After pathogen infection, the NLRs form large signaling platforms called inflammasomes, which lead to caspase-1 activation and maturation of proinflammatory cytokines (IL-18 and IL-1β). In this study, we showed that NLR family pyrin domain-containing 3 (Nlrp3) is required to induce caspase-1 activation and further secretion of IL-1β and IL-18 by P. brasiliensis-infected macrophages. Additionally, potassium efflux and lysosomal acidification induced by the fungus were important steps in the caspase-1 activation mechanism. Notably, Nlrp3 and caspase-1 knockout mice were more susceptible to infection than were the wild-type animals, suggesting that the Nlrp3-dependent inflammasomes contribute to host protection against P. brasiliensis. This protective effect occurred owing to the inflammatory response mediated by IL-18, as shown by an augmented fungus burden in IL-18 knockout mice. Taken together, our results show that the Nlrp3 inflammasome is essential for resistance against P. brasiliensis because it orchestrates robust caspase-1 activation and triggers an IL-18-dependent proinflammatory response.
病原体由先天免疫受体感知，这些受体在激活后引发有效的适应性免疫反应。巴西副球孢子菌先天免疫识别过程的要素包括TLR-2、TLR-4和dectin-1。然而，宿主对巴西副球孢子菌的免疫反应还需要其他受体。激活炎性小体的核苷酸结合寡聚化结构域样受体（NLRs）是值得重新研究的候选受体。病原体感染后，NLRs形成称为炎性小体的大型信号平台，导致半胱天冬酶-1激活和促炎细胞因子（IL-18和IL-1β）成熟。在本研究中，我们表明，巴西副球孢子菌感染的巨噬细胞诱导半胱天冬酶-1激活以及进一步分泌IL-1β和IL-18需要含NLR家族pyrin结构域3（Nlrp3）。此外，真菌诱导的钾外流和溶酶体酸化是半胱天冬酶-1激活机制中的重要步骤。值得注意的是，Nlrp3和半胱天冬酶-1基因敲除小鼠比野生型动物更容易感染，这表明Nlrp3依赖性炎性小体有助于宿主抵抗巴西副球孢子菌。如IL-18基因敲除小鼠中真菌负荷增加所示，这种保护作用是由于IL-18介导的炎症反应所致。综上所述，我们的结果表明，Nlrp3炎性小体对于抵抗巴西副球孢子菌至关重要，因为它协调强大的半胱天冬酶-1激活并触发IL-18依赖性促炎反应。
