Department of Respiration, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
Department of Respiration, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Biochem J. 2018 Jun 21;475(12):1995-2008. doi: 10.1042/BCJ20180086.
Activation of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome received substantial attention recently in inflammatory diseases. Macrophages contribute to allergic inflammation in asthma. The present study was aimed to investigate the effect of NLRP3 inflammasome on the polarization of macrophages. We utilized human primary monocytes and monocyte-derived macrophages to study the expression of NLRP3 inflammasome components (NLRP3, apoptosis-associated specklike protein, and caspase-1) and its downstream cytokine interleukin-1β (IL-1β). By gain- or loss-of-function assays, we next explored the effects of NLRP3 inflammasome on M1/M2 polarization and secretion of IL-4, interferon-γ, tumor necrosis factor-α, and IL-1β. The results showed increased numbers of M2 cells in asthma. And NLRP3 inflammasome was activated and involved in the inflammation of asthma. Furthermore, silence of NLRP3 down-regulated IL-4 secretion and up-regulated M1/M2. In contrast, overexpression of NLRP3 increased IL-4 and decreased M1/M2. As expected, IL-4 was involved in NLRP3-mediated down-regulation of Ml/M2 ratio. Moreover, NLRP3 interacted with IRF4 and was required for optimal IRF4-dependent IL-4 transcription. Subsequently, deficiency of NLRP3 in ovalbumin-induced allergic asthmatic mice impaired lung inflammation and up-regulated M1/M2, and diminished IL-4 in bronchoalveolar lavage fluid. Collectively, we demonstrated here that activation of NLRP3 was engaged in the promotion of asthma. NLRP3, but not the inflammasome adaptor ASC or caspase-1, promoted the polarization of M2 macrophages through up-regulating the expression of IL-4, thereby contributing to its regulation of asthma.
核苷酸结合寡聚化结构域样受体蛋白 3（NLRP3）炎性小体的激活最近在炎症性疾病中受到了广泛关注。巨噬细胞在哮喘的过敏炎症中起作用。本研究旨在研究 NLRP3 炎性小体对巨噬细胞极化的影响。我们利用人原代单核细胞和单核细胞衍生的巨噬细胞研究 NLRP3 炎性小体成分（NLRP3、凋亡相关斑点样蛋白和半胱天冬酶-1）及其下游细胞因子白细胞介素-1β（IL-1β）的表达。通过获得或丧失功能测定，我们接下来研究了 NLRP3 炎性小体对 M1/M2 极化和 IL-4、干扰素-γ、肿瘤坏死因子-α和 IL-1β分泌的影响。结果表明，哮喘中 M2 细胞数量增加。NLRP3 炎性小体被激活并参与哮喘的炎症。此外，NLRP3 的沉默下调了 IL-4 的分泌并上调了 M1/M2。相反，NLRP3 的过表达增加了 IL-4 并减少了 M1/M2。正如预期的那样，IL-4 参与了 NLRP3 介导的 M1/M2 比值下调。此外，NLRP3 与 IRF4 相互作用，是最佳 IRF4 依赖性 IL-4 转录所必需的。随后，卵清蛋白诱导的变应性哮喘小鼠中 NLRP3 的缺乏损害了肺炎症，并上调了 M1/M2，减少了支气管肺泡灌洗液中的 IL-4。总之，我们在这里证明了 NLRP3 的激活参与了哮喘的促进。NLRP3，而不是炎性小体衔接蛋白 ASC 或半胱天冬酶-1，通过上调 IL-4 的表达促进 M2 巨噬细胞的极化，从而有助于其对哮喘的调节。
