Soluble CD13 induces inflammatory arthritis by activating the bradykinin receptor B1
Pei-Suen Tsou, … , David A. Fox, M. Asif Amin
Pei-Suen Tsou, … , David A. Fox, M. Asif Amin
Published April 19, 2022
Citation Information: J Clin Invest. 2022;132(11):e151827. https://doi.org/10.1172/JCI151827.
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Research Article Autoimmunity

Soluble CD13 induces inflammatory arthritis by activating the bradykinin receptor B1

Abstract

CD13, an ectoenzyme on myeloid and stromal cells, also circulates as a shed, soluble protein (sCD13) with powerful chemoattractant, angiogenic, and arthritogenic properties, which require engagement of a G protein–coupled receptor (GPCR). Here we identify the GPCR that mediates sCD13 arthritogenic actions as the bradykinin receptor B1 (B1R). Immunofluorescence and immunoblotting verified high expression of B1R in rheumatoid arthritis (RA) synovial tissue and fibroblast-like synoviocytes (FLSs), and demonstrated binding of sCD13 to B1R. Chemotaxis, and phosphorylation of Erk1/2, induced by sCD13, were inhibited by B1R antagonists. In ex vivo RA synovial tissue organ cultures, a B1R antagonist reduced secretion of inflammatory cytokines. Several mouse arthritis models, including serum transfer, antigen-induced, and local innate immune stimulation arthritis models, were attenuated in Cd13–/– and B1R–/– mice and were alleviated by B1R antagonism. These results establish a CD13/B1R axis in the pathogenesis of inflammatory arthritis and identify B1R as a compelling therapeutic target in RA and potentially other inflammatory diseases.

Authors

Pei-Suen Tsou, Chenyang Lu, Mikel Gurrea-Rubio, Sei Muraoka, Phillip L. Campbell, Qi Wu, Ellen N. Model, Matthew E. Lind, Sirapa Vichaikul, Megan N. Mattichak, William D. Brodie, Jonatan L. Hervoso, Sarah Ory, Camila I. Amarista, Rida Pervez, Lucas Junginger, Mustafa Ali, Gal Hodish, Morgan M. O’Mara, Jeffrey H. Ruth, Aaron M. Robida, Andrew J. Alt, Chengxin Zhang, Andrew G. Urquhart, Jeffrey N. Lawton, Kevin C. Chung, Tristan Maerz, Thomas L. Saunders, Vincent E. Groppi, David A. Fox, M. Asif Amin

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Figure 5

Blockade of B1R attenuates ZIA and K/BxN serum transfer arthritis in mice.

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Blockade of B1R attenuates ZIA and K/BxN serum transfer arthritis in mic...
(A) B1R antagonist SSR240612 significantly reduced ZIA in WT mice compared with vehicle-treated mice. n = number of mice per group: PBS, n = 5; zymosan, n = 10; zymosan + SSR, n = 10. (B) Knee homogenates from SSR240612-treated mice showed significantly lower IL-1β and IL-6 in comparison with vehicle-treated mice. n = number of mouse knees per group: PBS, n = 3; zymosan, n = 5; zymosan + SSR, n = 5. (C) Immunofluorescence of knees from SSR240612-treated mice shows a marked decrease in macrophage marker F4/80 (green). Representative sections from each group are shown. Original magnification, ×200. (D) Vehicle-treated WT mice (n = 9–13) had profound serum transfer arthritis as measured by joint circumference compared with SSR240612-treated WT mice (n = 10). There was no difference in arthritis between SSR240612-treated Cd13–/– mice (n = 6) and vehicle-treated Cd13–/– mice (n = 10) except for day 8. (E) Significant decrease in MCP-1/CCL2 and IL-6 in ankle homogenates from SSR240612-treated WT (n = 9) compared with vehicle-treated WT mice (n = 13) is shown. In contrast, significant increase in the cytokines was observed in the SSR240612-treated Cd13–/– mice (n = 8) compared with vehicle-treated Cd13–/– mice (n = 6). (F) SSR240612-treated WT and Cd13–/– mouse cryosections showed a marked decrease in F4/80 staining compared with sections from vehicle-treated mice. Red staining represents F4/80 for MNs/macrophages, while blue (DAPI) stains nucleus. Original magnification, ×200. Results are expressed as mean ± SD. *P < 0.05. Significance was determined by Kruskal-Wallis test (A and E), 1-way ANOVA (B and F), and 2-way ANOVA (D).