Wang, Hui1, Li, Xiaofei, Kajikawa1, Tetsuhiro, Lim1, Jong-Hyung1, Chavakis, Triantafyllos2, Hajishengallis, George1
1University of Pennsylvania School of Dental Medicine, Department of Basic and Translational Sciences
2Technische Universität Dresden, Institute for Clinical Chemistry and Laboratory Medicine
Rheumatoid arthritis (RA) is a chronic autoimmune disease. The mechanisms of RA are poorly understood and currently there are no effective treatments. We previously showed that the secreted protein DEL-1 (developmental endothelial locus-1) acts as an endogenous anti-inflammatory factor in periodontitis. Here, our aim was to study whether DEL-1 can restrain RA in a mouse model and dissect the underlying mechanism.Methods
Collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) models were employed to test the anti-arthritogenic effects of DEL-1 using mice with endothelial-specific overexpression of DEL-1, collagen VI-specific overexpression of DEL-1, and DEL-1-deficient mice. DEL-1 expression levels were detected by RNAscope and immunohistochemistry. Hematoxylin/eosin and safranin-O staining were performed to detect tissue pathology and inflammatory cells. Immunologic parameters were tested by flow cytometry, RT-PCR and ELISA.Results
In both CIA and CAIA models of inflammatory arthritis, mice with endothelial-specific overexpression of DEL-1 were protected from arthritis relative to wild-type controls, while arthritis was exacerbated in DEL-1-deficient mice. Endothelial-derived DEL-1 was associated with diminished recruitment of inflammatory leukocytes to the joints. In comparison to wild-type 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 antibody response. Indeed, lymph node stromal cell-derived DEL-1 inhibited T follicular helper (Tfh) and germinal center B cell responses. Mechanistically, DEL-1 inhibited dendritic cell-dependent induction of Tfh cells by targeting the LFA-1 integrin on T cells.Conclusion
DEL-1 restrains 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.