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 2

sCD13 is a new ligand for B1R.

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sCD13 is a new ligand for B1R. (A) Western blot of RA FLSs preincubated ...
(A) Western blot of RA FLSs preincubated with sCD13 with or without addition of a BS3 cross-linker. A 40 kDa protein band was identified as the B1R monomer (labeled as B1R), and a 180 kDa band (labeled as B1R+sCD13), corresponding to the sum of the molecular masses of sCD13 plus B1R, was identified by both B1R and CD13 antibodies. (B) Immunofluorescence was performed to detect B1R on RA FLSs. RA FLSs were stained with an anti-B1R antibody (red), and nuclei were stained by DAPI (blue). Preincubation of RA FLSs with sCD13 blocked the binding of anti-B1R antibody to B1R (right panel). Original magnification, ×200. Experiments were performed twice. (C) C-I-TASSER program was used to predict the protein structure of monomeric B1R and CD13. Structure of the complex between B1R (colored in spectrum, with blue to red for N- to C-terminal) and CD13 (white, magenta, and black for its N-terminal, center, and C-terminal domains, respectively) is shown.