Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Mol Ther. 2021 Mar 3;29(3):1294-1311. doi: 10.1016/j.ymthe.2020.12.001. Epub 2020 Dec 3.
Tissue-resident macrophages (TRMs) are sentinel cells for maintaining tissue homeostasis and organ function. In this study, we discovered that lipopolysaccharide (LPS) administration dramatically reduced TRM populations and suppressed their self-renewal capacities in multiple organs. Using loss- and gain-of-function approaches, we define Sectm1a as a novel regulator of TRM self-renewal. Specifically, at the earlier stage of endotoxemia, Sectm1a deficiency exaggerated acute inflammation-induced reduction of TRM numbers in multiple organs by suppressing their proliferation, which was associated with more infiltrations of inflammatory monocytes/neutrophils and more serious organ damage. By contrast, administration of recombinant Sectm1a enhanced TRM populations and improved animal survival upon endotoxin challenge. Mechanistically, we identified that Sectm1a-induced upregulation in the self-renewal capacity of TRM is dependent on GITR-activated T helper cell expansion and cytokine production. Meanwhile, we found that TRMs may play an important role in protecting local vascular integrity during endotoxemia. Our study demonstrates that Sectm1a contributes to stabling TRM populations through maintaining their self-renewal capacities, which benefits the host immune response to acute inflammation. Therefore, Sectm1a may serve as a new therapeutic agent for the treatment of inflammatory diseases.
组织驻留巨噬细胞（TRMs）是维持组织内稳态和器官功能的哨兵细胞。在这项研究中，我们发现脂多糖（LPS）处理显著减少了 TRM 群体，并抑制了它们在多个器官中的自我更新能力。通过缺失和获得功能的方法，我们将 Sectm1a 定义为 TRM 自我更新的一个新调节因子。具体而言，在早期内毒素血症中，Sectm1a 缺乏通过抑制其增殖，加剧了急性炎症诱导的 TRM 数量在多个器官中的减少，这与更多炎症单核细胞/中性粒细胞的浸润和更严重的器官损伤有关。相比之下，重组 Sectm1a 的给药增加了 TRM 群体，并改善了内毒素挑战时动物的存活率。在机制上，我们确定 Sectm1a 诱导的 TRM 自我更新能力的上调依赖于 GITR 激活的辅助性 T 细胞的扩增和细胞因子的产生。同时，我们发现 TRMs 在保护内毒素血症期间局部血管完整性方面可能发挥重要作用。我们的研究表明，Sectm1a 通过维持其自我更新能力有助于稳定 TRM 群体，这有利于宿主对急性炎症的免疫反应。因此，Sectm1a 可能成为治疗炎症性疾病的一种新的治疗剂。
