The Major Chromoblastomycosis Etiologic Agent Fonsecaea pedrosoi Activates the NLRP3 Inflammasome.
The Major Chromoblastomycosis Etiologic Agent Fonsecaea pedrosoi Activates the NLRP3 Inflammasome.
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DOI：
10.3389/fimmu.2017.01572
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发表时间：
2017
影响因子：
7.3
通讯作者：
Bocca AL
中科院分区：
文献类型：
--
作者：
de Castro RJA;Siqueira IM;Jerônimo MS;Basso AMM;Veloso Junior PHH;Magalhães KG;Leonhardt LC;de Oliveira SAM;Bürgel PH;Tavares AH;Bocca AL
着色芽生菌病（chromoblastomycosis，CBM）是热带和亚热带国家最流行的皮下真菌病之一，其主要病原体是真菌丰塞菌。CBM是一种特征不明显的慢性感染，通常在分生孢子和腐殖菌丝经皮接种后开始。小儿科。最近，我们发现，与分生孢子不同，菌丝和鼠形细胞（寄生形态型）。pedroxacin在体内促进强烈的炎症反应模式，其包括炎性小体衍生的细胞因子IL-1β的产生。尽管如此，F.小儿感染及其在CBM过程中的功能输出仍然未知。我们在这里表明，F。与分生孢子不同，毛癣菌菌丝诱导骨髓来源的树突状细胞和巨噬细胞分泌IL-1β。使用抑制剂和敲除细胞，我们证明了由菌丝感染的巨噬细胞产生IL-1β的潜在机制依赖于dectin-1、-2和-3受体以及Syk-NF-kB信号通路。此外，F. pedrovaline促进NLRP 3依赖性炎性小体活化，其需要钾流出、活性氧产生、吞噬溶酶体酸化和组织蛋白酶B释放作为触发剂。IL-1β的加工和释放主要由caspase-1介导，在较小程度上由caspase-8依赖性裂解介导。最后，我们使用小鼠CBM模型表明，F。在体内，pedroplecelena NLRP 3调节IL-1β和白细胞介素-18的释放，但在实验感染过程中没有NLRP 3炎性体激活干扰。
Fonsecaea pedrosoi is the main etiologic agent of chromoblastomycosis (CBM), one of the most prevalent subcutaneous mycosis in tropical and subtropical countries. CBM is a poorly characterized chronic infection that commonly starts after transcutaneous inoculation of conidia and saprophytic hyphae of F. pedrosoi. Recently, we have shown that unlike conidia, hyphae and muriform cells (the parasitic morphotype) of F. pedrosoi promotes an intense inflammatory response pattern in vivo, which comprises the production of an inflammasome-derived cytokine, IL-1β. Nonetheless, the mechanisms underlying IL-1β production and maturation upon F. pedrosoi infection and its functional output in the course of CBM remains unknown. We show here that F. pedrosoi hyphae, differently from conidia, induce IL-1β secretion in both bone marrow-derived dendritic cells and macrophages. Using inhibitors and knockout cells, we demonstrated that the mechanisms underlying IL-1β production by hyphae-infected macrophages were dependent on dectin-1, -2, and -3 receptors and the Syk-NF-kB signaling pathway. Furthermore, F. pedrosoi promoted a NLRP3-dependent inflammasome activation, which required potassium efflux, reactive oxygen species production, phagolysosomal acidification, and cathepsin B release as triggers. IL-1β processing and release was mediated primarily by caspase-1 and, to a lesser extent, by caspase-8-dependent cleavage. Finally, we showed using a murine CBM model that F. pedrosoi elicits a NLRP3-regulated IL-1β and interleukin-18 release in vivo, but without NLRP3 inflammasome activation interfering in the course of the experimental infection.