Soluble CD13 induces inflammatory arthritis by activating the bradykinin receptor B1
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
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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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 1

Cd13-knockout (Cd13–/–) mice develop less inflammation compared with WT mice when injected with TNF-α.

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Cd13-knockout (Cd13–/–) mice develop less inflammation compared with WT ...
TNF-α was injected into Cd13–/– and C57BL/6J WT mouse knee joints. PBS served as a negative control. (A) Cd13–/– mice developed significantly less knee swelling when TNF-α was injected into their knees compared with WT mice. n = number of knee joints per group: WT-PBS, n = 16; WT–TNF-α, n = 18; Cd13–/–-PBS, n = 16; Cd13–/––TNF-α, n = 10. (B) sCD13 was significantly elevated in TNF-α–injected knees (n = 8) in WT mice compared with PBS-injected mice (n = 7). (C) Knee homogenates from TNF-α–treated WT mice (n = 9) showed significantly higher MCP-1/CCL2 and IL-1β compared with TNF-α–treated Cd13–/– mice (n = 11). n = number of mouse knees per group. (D) TNF-α–treated WT mouse cryosections showed a marked increase in F4/80 staining compared with sections from PBS-treated mice, and this was not observed in the TNF-α–treated Cd13–/– 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 C), unpaired, 2-tailed Student’s t test (B), and 1-way ANOVA (C and D).