The NLRP3 inflammasome, a caspase‐1 activation platform, plays a key role in the modulation of liver inflammation and fibrosis. Here, we tested the hypothesis that interleukin 17 (IL‐17) and tumor necrosis factor (TNF) are key cytokines involved in amplifying and perpetuating the liver damage and fibrosis resulting from NLRP3 activation. To address this hypothesis, gain‐of‐function Nlrp3A350V knock‐in mice were bred onto il17a and Tnf knockout backgrounds allowing for constitutive Nlrp3 activation in myeloid derived cells in mice deficient in IL‐17 or TNF. Livers of Nlrp3A350V knock‐in mice exhibited severe liver inflammatory changes characterized by infiltration with neutrophils, increased expression of chemokine (C‐X‐C motif) ligand (CXCL) 1 and CXCL2 chemokines, activated inflammatory macrophages, and elevated levels of IL‐17 and TNF. Mutants with ablation of il17a signal showed fewer neutrophils when compared to intact Nlrp3A350V mutants, but still significant inflammatory changes when compared to the nonmutant il17a knockout littermates. The severe inflammatory changes associated with mutant Nlrp3 were almost completely rescued by Tnf knockout in association with a marked decrease in circulating IL‐1β levels. Intact Nlrp3A350Vmutants showed changes in liver fibrosis, as evidenced by morphometric quantitation of Sirius Red staining and increased mRNA levels of profibrotic genes, including connective tissue growth factor and tissue inhibitor of matrix metalloproteinase 1. Il17a lacking mutants exhibited amelioration of the aforementioned fibrosis, whereas Tnf‐deficient mutants showed no signs of fibrosis when compared to littermate controls. Conclusion: Our study uncovers key roles for TNF and, to a lesser extent, IL‐17 as mediators of liver inflammation and fibrosis induced by constitutive NLRP3 inflammasome activation in myeloid‐derived cells. These findings may lead to therapeutic strategies aimed at halting the progression of liver injury and fibrogenesis in various liver pathogeneses driven by NLRP3 activation. (Hepatology 2018;67:736‐749).

中文翻译：

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NLRP3 炎症小体驱动的肝损伤和纤维化：IL-17 和 TNF 的作用

NLRP3 炎症小体是一种 caspase-1 激活平台，在肝脏炎症和纤维化的调节中起关键作用。在这里，我们检验了白细胞介素 17 (IL-17) 和肿瘤坏死因子 (TNF) 是参与放大和持续由 NLRP3 激活引起的肝损伤和纤维化的关键细胞因子的假设。为了解决这个假设，功能获得性 Nlrp3A350V 敲入小鼠被培育到 il17a 和 Tnf 敲除背景上，允许在缺乏 IL-17 或 TNF 的小鼠的骨髓衍生细胞中组成性 Nlrp3 激活。Nlrp3A350V 敲入小鼠的肝脏表现出严重的肝脏炎症变化，其特征是中性粒细胞浸润、趋化因子（C-X-C 基序）配体（CXCL）1 和 CXCL2 趋化因子的表达增加、激活的炎性巨噬细胞和 IL-17 水平升高和 TNF。与完整的 Nlrp3A350V 突变体相比，具有 il17a 信号消融的突变体显示出较少的中性粒细胞，但与非突变体 il17a 敲除同窝仔相比，仍存在显着的炎症变化。与突变 Nlrp3 相关的严重炎症变化几乎完全被 Tnf 敲除以及循环 IL-1β 水平的显着降低所挽救。完整的 Nlrp3A350V 突变体显示肝纤维化的变化，如天狼星红染色的形态计量学定量和促纤维化基因的 mRNA 水平增加所证明，包括结缔组织生长因子和基质金属蛋白酶 1 的组织抑制剂。缺乏突变体的 Il17a 表现出上述纤维化的改善，而 Tnf与同窝对照相比，缺陷突变体没有显示出纤维化的迹象。结论：我们的研究揭示了 TNF 的关键作用，在较小程度上，IL-17 作为由骨髓衍生细胞中的组成型 NLRP3 炎症小体激活诱导的肝脏炎症和纤维化的介质。这些发现可能导致旨在阻止由 NLRP3 激活驱动的各种肝脏病原体中肝损伤和纤维化进展的治疗策略。（肝病学 2018 年；67：736-749）。