A Novel CD206 Targeting Peptide Inhibits Bleomycin-Induced Pulmonary Fibrosis in Mice

Area of Science:

• Immunology
• Pulmonary Medicine
• Drug Discovery

Background:

• Activated M2-polarized macrophages drive pulmonary fibrosis, a key feature of Idiopathic Pulmonary Fibrosis (IPF).
• Targeting CD206 on M2 macrophages presents a potential therapeutic strategy for fibrosis.

Purpose of the Study:

• To investigate the antifibrotic effects of RP-832c, a novel Host Defense Peptide (HDP) analogue, by targeting the CD206 receptor on M2-like macrophages.
• To assess RP-832c's efficacy in reducing profibrotic cytokines and fibrosis in preclinical models.

Main Methods:

• In vitro studies using M2-polarized bone marrow-derived macrophages (BMDM) to assess RP-832c binding to CD206 and its effect on macrophage polarization.
• In vivo studies using murine models of bleomycin (BLM)-induced pulmonary fibrosis to evaluate RP-832c's antifibrotic activity, cytokine modulation, and comparison with FDA-approved drugs.

Main Results:

• RP-832c selectively bound to CD206 on M2 BMDM, decreasing CD206 expression and transiently increasing TNF-α.
• RP-832c significantly reduced lung fibrosis in a dose-dependent manner in BLM-induced models, decreasing CD206, TGF-β1, and α-SMA.
• RP-832c decreased inflammatory cytokines (TNF-α, IL-6, IL-10, IFN-γ, CXCL1/2) and fibrosis markers (TGF-β1, MMP-13) in established lung fibrosis models.
• RP-832c demonstrated comparable or superior fibrosis reduction to Pirfenidone and Nintedanib, respectively, with no observed toxicities.

Conclusions:

• Inhibiting profibrotic M2-like macrophages with RP-832c effectively reduces bleomycin-induced pulmonary fibrosis in mice.
• RP-832c exhibits therapeutic potential for treating pulmonary fibrosis, including IPF, warranting further clinical investigation.