Macrophage polarization to proinflammatory M1-like or anti-inflammatory M2-like cells is critical to mount a host defense or repair tissue. The exact molecular mechanisms controlling this process are still elusive. Here, we report that ubiquitin-specific protease 19 (USP19) acts as an anti-inflammatory switch that inhibits inflammatory responses and promotes M2-like macrophage polarization. USP19 inhibited NLRP3 inflammasome activation by increasing autophagy flux and decreasing the generation of mitochondrial reactive oxygen species. In addition, USP19 inhibited the proteasomal degradation of inflammasome-independent NLRP3 by cleaving its polyubiquitin chains. USP19-stabilized NLRP3 promoted M2-like macrophage polarization by direct association with interferon regulatory factor 4, thereby preventing its p62-mediated selective autophagic degradation. Consistent with these observations, compared to wild-type mice, Usp19^−/− mice had decreased M2-like macrophage polarization and increased interleukin-1β secretion, in response to alum and chitin injections. Thus, we have uncovered an unexpected mechanism by which USP19 switches the proinflammatory function of NLRP3 into an anti-inflammatory function, and suggest that USP19 is a potential therapeutic target for inflammatory interventions.

巨噬细胞极化为促炎性 M1 样或抗炎性 M2 样细胞对于建立宿主防御或修复组织至关重要。控制这一过程的确切分子机制仍然难以捉摸。在这里，我们报告泛素特异性蛋白酶 19 (USP19) 作为一种抗炎开关，可抑制炎症反应并促进 M2 样巨噬细胞极化。USP19 通过增加自噬通量和减少线粒体活性氧的产生来抑制 NLRP3 炎症小体的活化。此外，USP19 通过切割其多泛素链来抑制炎症小体非依赖性 NLRP3 的蛋白酶体降解。USP19 稳定的 NLRP3 通过与干扰素调节因子 4 直接关联促进 M2 样巨噬细胞极化，从而防止其p62介导的选择性自噬降解。与这些观察结果一致，与野生型小鼠相比，响应于明矾和几丁质注射， Usp19 ^-/-小鼠的 M2 样巨噬细胞极化减少，白细胞介素 1β 分泌增加。因此，我们发现了一种意想不到的机制，通过这种机制，USP19 将 NLRP3 的促炎功能转变为抗炎功能，并表明 USP19 是炎症干预的潜在治疗靶点。