The Journal of clinical investigation · 2022
Soluble CD13 induces inflammatory arthritis by activating the bradykinin receptor B1.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Tsou Pei-Suen, Lu Chenyang, Gurrea-Rubio Mikel, Muraoka Sei, Campbell Phillip L, Wu Qi, Model Ellen N, Lind Matthew E, Vichaikul Sirapa, Mattichak Megan N, Brodie William D, Hervoso Jonatan L, Ory Sarah, Amarista Camila I, Pervez Rida, Junginger Lucas, Ali Mustafa, Hodish Gal, O'Mara Morgan M, Ruth Jeffrey H, Robida Aaron M, Alt Andrew J, Zhang Chengxin, Urquhart Andrew G, Lawton Jeffrey N, Chung Kevin C, Maerz Tristan, Saunders Thomas L, Groppi Vincent E, Fox David A, Amin M Asif
Аннотация
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.