Stromal cell–derived DEL-1 inhibits Tfh cell activation and inflammatory arthritis
| Autor: | Ioannis Kourtzelis, Tetsuhiro Kajikawa, Jieun Shin, Jonathan Korostoff, Jong-Hyung Lim, George Hajishengallis, Hui Wang, Xiaofei Li, Ronald Naumann, Triantafyllos Chavakis, Kosuke Nagai, Sylvia Grossklaus |
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| Rok vydání: | 2021 |
| Předmět: |
Male
congenital hereditary and neonatal diseases and abnormalities Stromal cell T Follicular Helper Cells Inflammatory arthritis Arthritis Lymphocyte Activation medicine.disease_cause Autoimmunity Mice medicine Animals Antigen-presenting cell B cell business.industry Calcium-Binding Proteins Germinal center Cell Differentiation General Medicine Germinal Center medicine.disease Arthritis Experimental Lymphocyte Function-Associated Antigen-1 Mice Inbred C57BL medicine.anatomical_structure Cancer research Female Stromal Cells Cell activation business Cell Adhesion Molecules Research Article |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 |
| DOI: | 10.1172/jci150578 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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