Stromal cell-derived DEL-1 inhibits Tfh cell activation and inflammatory arthritis.

Abstract

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.

• Authors: Hui Wang, Xiaofei Li, Tetsuhiro Kajikawa, Jieun Shin, Jong-Hyung Lim, Ioannis Kourtzelis, Kosuke Nagai, Jonathan M Korostoff, Sylvia Grossklaus, Ronald Naumann, Triantafyllos Chavakis, George Hajishengallis
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 131 Issue 19 (10 01 2021) ISSN: 1558-8238 [Electronic] United States
• PMID: 34403362 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium-Binding Proteins
• Cell Adhesion Molecules
• Edil3 protein, mouse
• Lymphocyte Function-Associated Antigen-1

Topics

• Animals
• Arthritis, Experimental (prevention & control)
• Calcium-Binding Proteins (physiology)
• Cell Adhesion Molecules (physiology)
• Cell Differentiation
• Female
• Germinal Center (immunology)
• Lymphocyte Activation
• Lymphocyte Function-Associated Antigen-1 (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Stromal Cells (chemistry)
• T Follicular Helper Cells (cytology, immunology)