Muraoka Sei, Brodie William D, Mattichak Megan N, Gurrea-Rubio Mikel, Ikari Yuzo, Foster Caroline, Amin M Asif, Khanna Neha, Amin Hafsa, Campbell Phillip L, Vichaikul Sirapa, Model Ellen N, Omara Morgan M, Petrovski Steven, Kozicki Karly, Amarista Camilia, Webber Anna, Ali Mustafa, Palisoc Pamela J, Hervoso Jonatan, Ruth Jeffrey H, Tsoi Lam C, Varga John, Gudjonsson Johann E, Khanna Dinesh, Fox David A, Tsou Pei-Suen
University of Michigan, Ann Arbor, and Toho University School of Medicine, Tokyo, Japan.
University of Michigan, Ann Arbor.
Arthritis Rheumatol. 2025 Jan;77(1):80-91. doi: 10.1002/art.42973. Epub 2024 Sep 18.
Systemic sclerosis (SSc) is an autoimmune multisystem disease with poorly understood pathogenesis and ineffective treatment options. Soluble CD13 (sCD13), generated by the cleavage of cell surface CD13 via matrix metalloproteinase 14 (MMP14), signals through the bradykinin receptor B1 (B1R) to elicit pro-inflammatory, pro-arthritic, and pro-angiogenic responses. In this study, we explored the antifibrotic potential of targeting the sCD13-B1R axis in SSc.
The expression of CD13, B1R, and MMP14 was examined in SSc skin and explanted dermal fibroblasts. The efficacy of B1R antagonists in the inhibition on fibrosis was determined in vitro and in vivo.
Expression of the genes for CD13, B1R, and MMP14 was elevated in skin biopsies from patients with diffuse cutaneous (dc) SSc. Notably, single-cell analysis of SSc skin biopsies revealed the highest BDKRB1 expression in COL8A1-positive myofibroblasts, a population exclusively seen in SSc. Transforming growth factor beta (TGFβ) induced the expression of BDKRB1 and production of sCD13 by dcSSc skin fibroblasts. Treatment of dcSSc fibroblasts with sCD13 promoted fibrotic gene expression, signaling, cell proliferation, migration, and gel contraction. The pro-fibrotic responses of sCD13 or TGFβ were prevented by a B1R antagonist. Mice lacking Cd13 or Bdkrb1 were resistant to bleomycin-induced skin fibrosis and inflammation. Pharmacological B1R inhibition had a comparable antifibrotic effect.
These results are the first to demonstrate a key role for sCD13 in SSc skin fibrosis and suggest that targeting the sCD13-B1R signaling axis is a promising novel therapeutic approach for SSc.
系统性硬化症（SSc）是一种自身免疫性多系统疾病，其发病机制尚不清楚，治疗选择也无效。可溶性CD13（sCD13）由基质金属蛋白酶14（MMP14）切割细胞表面CD13产生，通过缓激肽受体B1（B1R）发出信号，引发促炎、促关节炎和促血管生成反应。在本研究中，我们探讨了靶向SSc中sCD13-B1R轴的抗纤维化潜力。
检测SSc皮肤和外植真皮成纤维细胞中CD13、B1R和MMP14的表达。在体外和体内确定B1R拮抗剂对纤维化的抑制效果。
弥漫性皮肤（dc）SSc患者皮肤活检中CD13、B1R和MMP14基因的表达升高。值得注意的是，对SSc皮肤活检的单细胞分析显示，COL8A1阳性肌成纤维细胞中BDKRB1表达最高，这是SSc中特有的细胞群体。转化生长因子β（TGFβ）诱导dcSSc皮肤成纤维细胞中BDKRB1的表达和sCD13的产生。用sCD13处理dcSSc成纤维细胞可促进纤维化基因表达、信号传导、细胞增殖、迁移和凝胶收缩。B1R拮抗剂可阻止sCD13或TGFβ的促纤维化反应。缺乏Cd13或Bdkrb
1的小鼠对博来霉素诱导的皮肤纤维化和炎症具有抗性。药理学上抑制B1R具有类似的抗纤维化作用。
这些结果首次证明sCD13在SSc皮肤纤维化中起关键作用，并表明靶向sCD13-B1R信号轴是一种有前景的SSc新型治疗方法。
