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Stromal cell–derived DEL-1 inhibits Tfh cell activation and inflammatory arthritis
The Journal of Clinical Investigation ( IF 13.3 ) Pub Date : 2021 , DOI: 10.1172/jci150578
Hui Wang 1 , Xiaofei Li 1 , Tetsuhiro Kajikawa 1 , Jieun Shin 1 , Jong-Hyung Lim 1 , Ioannis Kourtzelis 2, 3 , Kosuke Nagai 2 , Jonathan M Korostoff 4 , Sylvia Grossklaus 2 , Ronald Naumann 5 , Triantafyllos Chavakis 2, 6 , George Hajishengallis 1
Affiliation  

The secreted protein developmental endothelial locus 1 (DEL-1) regulates inflammatory cell recruitment and protects against inflammatory pathologies in animal models. Here, we investigated DEL-1 in inflammatory arthritis using collagen-induced arthritis (CIA) and collagen Ab–induced arthritis (CAIA) models. In both models, mice with endothelium-specific overexpression of DEL-1 were protected from arthritis relative to WT controls, whereas arthritis was exacerbated in DEL-1–deficient mice. Compared with WT controls, mice with collagen VI promoter–driven overexpression of DEL-1 in mesenchymal cells were protected against CIA but not CAIA, suggesting a role for DEL-1 in the induction of the arthritogenic Ab response. Indeed, DEL-1 was expressed in perivascular stromal cells of the lymph nodes and inhibited Tfh and germinal center B cell responses. Mechanistically, DEL-1 inhibited DC-dependent induction of Tfh cells by targeting the LFA-1 integrin on T cells. Overall, DEL-1 restrained arthritis through a dual mechanism, one acting locally in the joints and associated with the anti-recruitment function of endothelial cell–derived DEL-1; the other mechanism acting systemically in the lymph nodes and associated with the ability of stromal cell–derived DEL-1 to restrain Tfh responses. DEL-1 may therefore be a promising therapeutic for the treatment of inflammatory arthritis.

中文翻译:


基质细胞衍生的 DEL-1 抑制 Tfh 细胞活化和炎症性关节炎



在动物模型中,分泌蛋白发育内皮基因座 1 (DEL-1) 调节炎症细胞募集并防止炎症病理。在这里,我们使用胶原诱导的关节炎 (CIA) 和胶原抗体诱导的关节炎 (CAIA) 模型研究了 DEL-1 在炎症性关节炎中的作用。在这两种模型中,与 WT 对照相比,内皮特异性过度表达 DEL-1 的小鼠免受关节炎的影响,而 DEL-1 缺陷小鼠的关节炎则加剧。与 WT 对照相比,间充质细胞中胶原蛋白 VI 启动子驱动的 DEL-1 过度表达的小鼠可以免受 CIA 的影响,但不能免受 CAIA 的影响,这表明 DEL-1 在诱导关节炎抗体反应中发挥着作用。事实上,DEL-1 在淋巴结血管周围基质细胞中表达,并抑制 Tfh 和生发中心 B 细胞反应。从机制上讲,DEL-1 通过靶向 T 细胞上的 LFA-1 整合素来抑制 Tfh 细胞的 DC 依赖性诱导。总体而言,DEL-1 通过双重机制抑制关节炎,一种机制局部作用于关节,并与内皮细胞衍生的 DEL-1 的抗复张功能相关;另一种机制在关节中发挥作用,并与内皮细胞衍生的 DEL-1 的抗复张功能相关。另一种机制在淋巴结中发挥全身作用,与基质细胞衍生的 DEL-1 抑制 Tfh 反应的能力相关。因此,DEL-1 可能是治疗炎症性关节炎的一种有前途的疗法。
更新日期:2021-10-02
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