R1R2 peptide ameliorates pulmonary fibrosis in mice through fibrocyte migration and differentiation

Abstract

Circulating fibrocytes play a key role in the pathogenesis of pulmonary fibrosis. Fibrocytes are bone marrow-derived leukocytes, which enter the lungs in response to their chemoattractant CXCL12 and differentiate into fibroblasts or myofibroblasts, leading to excess deposition of the collagen-rich extracellular matrix. Matrix metalloproteinase (MMP)-9 and MMP-2, secreted by fibrocytes, degrade the subendothelial basement membrane and promote fibrocyte influx into the lungs. Here, we demonstrate that R1R2, a novel peptide derived from the bacterial adhesin SFS, attenuates pulmonary fibrosis by preventing the differentiation of fibrocytes into myofibroblasts and by reducing the invasion of fibrocytes through basement membrane-like proteins. Moreover, our findings reveal dual regulation of R1R2 on MMP-9 through reduced enzymatic activity on gelatin and increased cleavage of CXCL12. These data suggest that R1R2 has potent anti-fibrotic effects against pulmonary fibrosis.