Paracoccidioidomycosis (PCM) is a systemic mycosis caused by thermally dimorphic fungi of the genus Paracoccidioides that affects predominantly 30-60-year-old male rural workers. The main clinical forms of the disease are acute/subacute, chronic (CF); almost all CF patients develop pulmonary fibrosis, and they also exhibit emphysema due to smoke. An important cytokine in this context, IL-1β, different from the others, is produced by an intracellular multimolecular complex called inflammasome that is activated by pathogens and/or host signs of damage. Inflammasome has been recognized for its contribution to chronic inflammatory diseases, from that, we hypothesized that this activation could be involved in paracoccidioidomycosis, contributing to chronic inflammation. While inflammasome activation has been demonstrated in experimental models of Paracoccidioides brasiliensis infection, no information is available in patients, leading us to investigate the participation of NLRP3-inflammasome machinery in CF/PCM patients from a Brazilian endemic area. Our findings showed increased priming in mRNA levels of NLRP3 inflammasome genes by monocytes of PCM patients in vitro than healthy controls. Similar intracellular protein expression of NLRP3, CASP-1, ASC, and IL-1β were also observed in freshly isolated monocytes of PCM patients and smoker controls. Increased expression of NLRP3 and ASC was observed in monocytes from PCM patients under hypoxia in comparison with smoker controls. For the first time, we showed that primed monocytes of CF-PCM patients were associated with enhanced expression of components of NLRP3-inflammasome due to smoke. Also, hypoxemia boosted this machinery. These findings reinforce the systemic low-grade inflammation activation observed in PCM during and after treatment.

中文翻译：

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肺副球虫病患者单核细胞增强的NLRP3炎性体成分表达与吸烟和细胞内低氧血症有关。

副球菌病（PCM）是由副球菌属的热二态真菌引起的全身性真菌病，主要影响30-60岁的男性农村工人。该疾病的主要临床形式是急性/亚急性，慢性（CF）；几乎所有的CF患者都发展为肺纤维化，并且还因吸烟而出现肺气肿。在这种情况下，重要的细胞因子IL-1β与其他细胞因子不同，是由称为炎症小体的细胞内多分子复合物产生的，该复合物被病原体和/或宿主受损迹象激活。炎性小体因其对慢性炎性疾病的贡献而得到公认，因此，我们推测这种激活可能与副球菌类真菌病有关，从而导致了慢性炎症。虽然在巴西副球菌感染的实验模型中证实了炎性体激活，但患者尚无相关信息，这使我们研究了来自巴西流行地区的CF / PCM患者中NLRP3炎性体机制的参与。我们的研究结果显示，与健康对照组相比，PCM患者单核细胞在NLRP3炎性小体基因的mRNA水平上的启动增强。在新鲜分离的PCM患者和吸烟者单核细胞中也观察到了类似的NLRP3，CASP-1，ASC和IL-1β胞内蛋白表达。与吸烟者对照相比，在缺氧状态下PCM患者的单核细胞中NLRP3和ASC的表达增加。首次，我们表明，CF-PCM患者的初免单核细胞与吸烟引起的NLRP3炎性小体成分增强表达有关。另外，低氧血症促进了这种机制。这些发现加强了在治疗期间和之后在PCM中观察到的全身性低度炎症激活。