Stromal cell–derived DEL-1 inhibits Tfh cell activation and inflammatory arthritis
Hui Wang, … , Triantafyllos Chavakis, George Hajishengallis
Hui Wang, … , Triantafyllos Chavakis, George Hajishengallis
Published August 17, 2021
Citation Information: J Clin Invest. 2021;131(19):e150578. https://doi.org/10.1172/JCI150578.
View: Text | PDF
Research Article Autoimmunity Inflammation

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

×

Figure 1

Del1-KO mice are more susceptible to CIA and CAIA relative to WT littermate controls.

Options: View larger image (or click on image) Download as PowerPoint
Del1-KO mice are more susceptible to CIA and CAIA relative to WT litter...
CIA was induced by i.d. injection of 2 mg/mL CII emulsified with 1 mg/mL CFA into the tail of Del1-KO mice and WT littermates. Joint thickness (A) and clinical arthritis scores (B) were recorded at indicated time points. (C) Total cell numbers in the synovium of knee joints in Del1-KO and WT mice on day 42. H&E (D) and safranin-O (E) staining of tissue sections from knee joints harvested on day 42. Scale bars: 500 μm. (F) Cell suspensions prepared from the synovium of knee joints (harvested on day 42) were processed for FACS to identify and quantify neutrophils (CD45+CD11b+F4/80–Ly6G+) and macrophages (CD45+CD11b+F4/80+). (G–L) CAIA was induced in Del1-KO mice and WT littermates by i.v. injection of arthritogenic mAbs (0.5 mg/mouse) at day 0, followed by i.p. injection of 50 μg LPS on day 3. Joint thickness (G) and clinical arthritis scores (H) were recorded every day. (I) Total cell numbers in the synovium of knee joints in Del1-KO and WT mice on day 7. H&E (J) and safranin-O (K) staining of tissue sections from knee joints harvested on day 7. Scale bars: 500 μm. (L) Cell suspensions prepared from the synovium of knee joints (harvested on day 7) were processed for FACS to identify and quantify neutrophils (CD45+CD11b+F4/80–Ly6G+) and macrophages (CD45+CD11b+F4/80+). Data are the mean ± SD (A, B, G, and H: n = 14 mice/group from 3 independent experiments; C, F, I, and L: n = 9 mice/group from 2 independent experiments). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Two-way ANOVA with repeated-measures and Sidak’s post tests for comparison with WT mice (A, B, G, and H); Mann-Whitney U test (C, F [left]); and Student’s unpaired t test (F [right], I, and L).