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Targeting CD13/Aminopeptidase N as a Novel Therapeutic Approach for Scleroderma Fibrosis
Sei Muraoka1, William D Brodie2, Megan N Mattichak2
1University of Michigan, Ann Arbor, and Toho University School of Medicine, Tokyo, Japan.
Objective:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Targeting the soluble CD13 (sCD13) and bradykinin receptor B1 (B1R) axis shows promise for treating systemic sclerosis (SSc). Inhibiting this pathway reduced fibrosis and inflammation in SSc models, offering a potential new therapeutic strategy.
Area of Science:
- Immunology and Rheumatology
- Dermatology
- Molecular Biology
Background:
- Systemic sclerosis (SSc) is an autoimmune disease with limited treatment options.
- The sCD13-B1R signaling pathway is implicated in pro-inflammatory and pro-fibrotic responses.
- Understanding SSc pathogenesis is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the antifibrotic potential of targeting the sCD13-B1R axis in SSc.
- To explore the role of sCD13 and B1R in SSc skin fibrosis.
Main Methods:
- Examined CD13, B1R, and MMP14 expression in SSc skin and fibroblasts.
- Assessed the efficacy of B1R antagonists in vitro and in vivo models of SSc.
- Utilized gene expression analysis, cell signaling assays, and mouse models of bleomycin-induced fibrosis.
Main Results:
- Elevated CD13, B1R, and MMP14 gene expression was observed in SSc skin.
- sCD13 and TGFβ promoted fibrotic responses in SSc fibroblasts, which were blocked by B1R antagonists.
- Mice lacking CD13 or B1R, and those treated with B1R inhibitors, showed reduced skin fibrosis and inflammation.
Conclusions:
- The sCD13-B1R axis plays a significant role in SSc skin fibrosis.
- Targeting the sCD13-B1R signaling pathway represents a novel and promising therapeutic strategy for SSc.
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