Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Emergency, Union Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, China.
J Clin Invest. 2019 Aug 5;129(9):3657-3669. doi: 10.1172/JCI127542.
Fibroblastic reticular cells (FRCs), a subpopulation of stromal cells in lymphoid organs and fat-associated lymphoid clusters (FALCs) in adipose tissue, play immune-regulatory roles in the host response to infection and may be useful as a form of cell therapy in sepsis. Here, we found an unexpected major role of TLR9 in controlling peritoneal immune cell recruitment and FALC formation at baseline and after sepsis induced by cecal ligation and puncture (CLP). TLR9 regulated peritoneal immunity via suppression of chemokine production by FRCs. Adoptive transfer of TLR9-deficient FRCs more effectively decreased mortality, bacterial load, and systemic inflammation after CLP than WT FRCs. Importantly, we found that activation of TLR9 signaling suppressed chemokine production by human adipose tissue-derived FRCs. Together, our results indicate that TLR9 plays critical roles in regulating peritoneal immunity via suppression of chemokine production by FRCs. These data form a knowledge basis upon which to design new therapeutic strategies to improve the therapeutic efficacy of FRC-based treatments for sepsis and immune dysregulation diseases.
纤维母细胞网状细胞（FRCs）是淋巴器官中的基质细胞亚群和脂肪组织中脂肪相关淋巴簇（FALCs）中的一种，在宿主对感染的免疫反应中发挥免疫调节作用，并且可能作为细胞疗法在败血症中有用。在这里，我们发现 TLR9 在控制腹膜炎免疫细胞募集和 FALC 形成方面具有出乎意料的主要作用，基线时以及通过盲肠结扎和穿刺（CLP）诱导败血症后都是如此。TLR9 通过抑制 FRC 产生趋化因子来调节腹膜免疫。与 WT FRC 相比，过继转移 TLR9 缺陷型 FRC 更有效地降低了 CLP 后的死亡率、细菌负荷和全身炎症。重要的是，我们发现 TLR9 信号的激活抑制了人脂肪组织来源的 FRC 产生趋化因子。总之，我们的结果表明，TLR9 通过抑制 FRC 产生趋化因子在调节腹膜免疫中发挥关键作用。这些数据为设计新的治疗策略提供了知识基础，以提高基于 FRC 的治疗败血症和免疫失调疾病的治疗效果。
