Gain-of-function mutations in NLRP3 are responsible for a spectrum of autoinflammatory diseases collectively referred to as “cryopyrin-associated periodic syndromes” (CAPS). Treatment of CAPS patients with IL-1–targeted therapies is effective, confirming a central pathogenic role for IL-1β. However, the specific myeloid cell population(s) exhibiting inflammasome activity and sustained IL-1β production in CAPS remains elusive. Previous reports suggested an important role for mast cells (MCs) in this process. Here, we report that, in mice, gain-of-function mutations in Nlrp3 restricted to neutrophils, and to a lesser extent macrophages/dendritic cells, but not MCs, are sufficient to trigger severe CAPS. Furthermore, in patients with clinically established CAPS, we show that skin-infiltrating neutrophils represent a substantial biological source of IL-1β. Together, our data indicate that neutrophils, rather than MCs, can represent the main cellular drivers of CAPS pathology.

中文翻译：

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Nlrp3 中性粒细胞特异性功能获得性突变促进低温吡啶相关周期性综合征的发展

NLRP3 中的功能获得性突变是导致一系列自身炎症性疾病的原因，这些疾病统称为“冷吡啉相关周期性综合征”（CAPS）。用 IL-1 靶向疗法治疗 CAPS 患者是有效的，证实了 IL-1β 的中心致病作用。然而，在 CAPS 中表现出炎性体活性和持续产生 IL-1β 的特定骨髓细胞群仍然难以捉摸。以前的报告表明肥大细胞（MC）在这个过程中的重要作用。在这里，我们报告说，在小鼠中，Nlrp3的功能获得突变仅限于中性粒细胞，以及在较小程度上巨噬细胞/树突状细胞，但不是 MC，足以引发严重的 CAPS。此外，在临床确定的 CAPS 患者中，我们发现皮肤浸润性中性粒细胞代表了 IL-1β 的重要生物学来源。总之，我们的数据表明，中性粒细胞，而不是 MC，可以代表 CAPS 病理学的主要细胞驱动因素。