Regulation of neutrophil activation is critical for disease control. Neutrophil extracellular traps (NETs), which are web-like structures composed of DNA and neutrophil-derived proteins, are formed following pro-inflammatory signals; however, if this process is uncontrolled, NETs contribute to disease pathogenesis, exacerbating inflammation and host tissue damage^1,2. Here we show that myeloid inhibitory C-type lectin-like (MICL), an inhibitory C-type lectin receptor, directly recognizes DNA in NETs; this interaction is vital to regulate neutrophil activation. Loss or inhibition of MICL functionality leads to uncontrolled NET formation through the ROS–PAD4 pathway and the development of an auto-inflammatory feedback loop. We show that in the context of rheumatoid arthritis, such dysregulation leads to exacerbated pathology in both mouse models and in human patients, where autoantibodies to MICL inhibit key functions of this receptor. Of note, we also detect similarly inhibitory anti-MICL autoantibodies in patients with other diseases linked to aberrant NET formation, including lupus and severe COVID-19. By contrast, dysregulation of NET release is protective during systemic infection with the fungal pathogen Aspergillus fumigatus. Together, we show that the recognition of NETs by MICL represents a fundamental autoregulatory pathway that controls neutrophil activity and NET formation.

中性粒细胞激活的调节对于疾病控制至关重要。中性粒细胞胞外陷阱 (NET) 是由 DNA 和中性粒细胞衍生蛋白组成的网状结构，是在促炎信号后形成的；然而，如果这个过程不受控制，NET 会导致疾病发病，加剧炎症和宿主组织损伤^1,2 。在这里，我们展示了髓样抑制性 C 型凝集素样 (MICL)，一种抑制性 C 型凝集素受体，可直接识别 NET 中的 DNA；这种相互作用对于调节中性粒细胞的激活至关重要。 MICL 功能的丧失或抑制导致通过 ROS-PAD4 途径不受控制的 NET 形成以及自身炎症反馈循环的发展。我们发现，在类风湿性关节炎的背景下，这种失调会导致小鼠模型和人类患者的病理恶化，其中 MICL 的自身抗体会抑制该受体的关键功能。值得注意的是，我们还在患有与异常 NET 形成相关的其他疾病（包括狼疮和重症 COVID-19）的患者中检测到类似的抑制性抗 MICL 自身抗体。相比之下，在真菌病原体烟曲霉的全身感染过程中，NET 释放的失调具有保护作用。我们共同证明 MICL 对 NET 的识别代表了控制中性粒细胞活动和 NET 形成的基本自动调节途径。