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

Abstract

The secreted protein 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). In both models, mice with endothelial-specific overexpression of DEL-1 were protected from arthritis relative to WT controls, while arthritis was exacerbated in DEL-1-deficient mice. Compared to 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 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. 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 thus be a promising novel therapeutic for the treatment of inflammatory arthritis.

Developmental endothelial locus-1 in cardiovascular and metabolic diseases: a promising biomarker and therapeutic target

“…However, excessive inflammation may exacerbate MI-induced myocardial injury [109,111]. DEL-1 has anti-inflammatory and pro-resolving effects, and the lack of DEL-1 may inhibit inflammation resolution, leading to excessive inflammatory response and aggravating tissue damage [40,60,112,113]. Therefore, the extent of the increased inflammation caused by DEL-1 deficiency in Wei et al's study requires further scrutiny.…”

The Differentiation and Maintenance of SARS-CoV-2-Specific Follicular Helper T Cells

“…Also, NOTCH1/2 deficiency in CD4 + T cell reduces the expression of BCL6, IL-21, and CXCR5, but increases Blimp-1 expression, resulting in impairment of the development and function of T FH cells. Additional factors have been verified in regulating T FH cell differentiation, including but not limited to the E3 ligase cullin 3 (Cul3) ( Mathew et al., 2014 ), heterotrimeric G protein Gα 13 ( Kuen et al., 2021 ), kinase PRKD2 ( Misawa et al., 2020 ), kinase PDK1 ( Sun et al., 2021 ), extracellular matrix protein 1 (ECM1) ( He et al., 2018 ), and stromal cell-derived DEL-1 ( Wang et al., 2021 ).…”

Developmental endothelial locus-1 in cardiovascular and metabolic diseases: A promising biomarker and therapeutic target

“…However, excessive inflammation may exacerbate MI-induced myocardial injury ( 109 , 111 ). DEL-1 has anti-inflammatory and proresolving effects, and the lack of DEL-1 may inhibit inflammatory resolution, leading to an excessive inflammatory response and exacerbating tissue damage ( 40 , 60 , 112 , 113 ). Therefore, the extent of the increased inflammation caused by DEL-1 deficiency in Wei et al.’s study requires further scrutiny.…”