近日，英国埃克塞特大学Gordon D. Brown小组发现，MICL识别并调控中性粒细胞胞外陷阱的形成。这一研究成果于2024年8月14日在线发表在国际学术期刊《自然》上。

研究人员发现髓样抑制性C型凝集素样受体（MICL），一种抑制性C型凝集素受体，能够直接识别中性粒细胞胞外陷阱（NET）中的DNA，这一相互作用对于调控中性粒细胞活化至关重要。MICL功能的丧失或抑制会通过ROS-PAD4通路导致失控的NET形成，并形成自体炎症反馈循环。研究人员发现，在类风湿性关节炎的背景下，这种失调会加重病理过程，不论是在小鼠模型还是在人类患者中，抗MICL自身抗体都会抑制该受体的关键功能。

值得注意的是，研究人员还在其他与NET形成异常相关的疾病患者中检测到类似的抑制性抗MICL自身抗体，包括系统性红斑狼疮和重症COVID-19。相比之下，在系统性感染病原真菌烟曲霉的情况下，NET释放的失调反而具有保护作用。总之，该研究表明，MICL识别NET代表了一条控制中性粒细胞活性和NET形成的重要自我调节途径。

据悉，中性粒细胞的活化调控对于疾病控制至关重要。NET是一种由DNA和中性粒细胞衍生蛋白组成的网状结构，在受到促炎信号后形成。然而，如果这种过程失控，NET会导致疾病发病机制，加剧炎症并对宿主组织造成损害。

附：英文原文

Title: Recognition and control of neutrophil extracellular trap formation by MICL

Author: Malamud, Mariano, Whitehead, Lauren, McIntosh, Alasdair, Colella, Fabio, Roelofs, Anke J., Kusakabe, Takato, Dambuza, Ivy M., Phillips-Brookes, Annie, Salazar, Fabin, Perez, Federico, Shoesmith, Romey, Zakrzewski, Przemyslaw, Sey, Emily A., Rodrigues, Cecilia, Morvay, Petruta L., Redelinghuys, Pierre, Bedekovic, Tina, Fernandes, Maria J. G., Almizraq, Ruqayyah, Branch, Donald R., Amulic, Borko, Harvey, Jamie, Stewart, Diane, Yuecel, Raif, Reid, Delyth M., McConnachie, Alex, Pickering, Matthew C., Botto, Marina, Iliev, Iliyan D., McInnes, Iain B., De Bari, Cosimo, Willment, Janet A., Brown, Gordon D.

Issue&Volume: 2024-08-14

Abstract: 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 damage1,2. 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.

DOI: 10.1038/s41586-024-07820-3

Source: https://www.nature.com/articles/s41586-024-07820-3