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

  • Cells. 2023 Apr 26;12(9):1254. doi: 10.3390/cells12091254.
Anghesom Ghebremedhin  1 ,  Ahmad Bin Salam  2 ,  Benjamin Adu-Addai  3 ,  Steve Noonan  4 ,  Richard Stratton  5 ,  Md Shakir Uddin Ahmed  2  6 ,  Chandra Khantwal  4 ,  George R Martin  7 ,  Huixian Lin  2 ,  Chris Andrews  2 ,  Balasubramanyam Karanam  2 ,  Udo Rudloff  8 ,  Henry Lopez  4 ,  Jesse Jaynes  9 ,  Clayton Yates  2
Affiliations
  • 1. Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
  • 2. Department of Biology and Center for Cancer Research, Tuskegee University, Carver Research Foundation, Tuskegee, AL 36088, USA.
  • 3. Department of Pathobiology, College of Veterinary Medicine, Tuskegee University, Tuskegee, AL 36088, USA.
  • 4. Murigenics Inc., 941 Railroad Ave., Vallejo, CA 94592, USA.
  • 5. Royal Free Hospital, UCL Division of Medicine, University College London, London WC1E 6JF, UK.
  • 6. Bangladesh Council of Scientific and Industrial Research, Dhaka 1205, Bangladesh.
  • 7. Riptide Bioscience, 941 Railroad Ave., Vallejo, CA 94592, USA.
  • 8. Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • 9. College of Agriculture, Environment and Nutrition Sciences, Tuskegee University, Tuskegee, AL 36088, USA.
PMID: 37174654 DOI: 10.3390/cells12091254
Abstract

Activated M2-polarized macrophages are drivers of pulmonary fibrosis in several clinical scenarios, including Idiopathic Pulmonary Fibrosis (IPF). In this study, we investigated the effects of targeting the CD206 receptor in M2-like macrophages with a novel synthetic analogue of a naturally occurring Host Defense Peptide (HDP), RP-832c, to decrease profibrotic cytokines. RP-832c selectively binds to CD206 on M2-polarized bone marrow-derived macrophages (BMDM) in vitro, resulting in a time-dependent decrease in CD206 expression and a transient increase in M1-macrophage marker TNF-α. To elucidate the antifibrotic effects of RP-832c, we used a murine model of bleomycin (BLM)-induced early-stage pulmonary fibrosis. RP-832c significantly reduced fibrosis in a dose-dependent manner, and decreased CD206, TGF-β1, and α-SMA expression in mouse lungs. Similarly, in an established model of lung fibrosis, RP-832c significantly decreased lung fibrosis and significantly decreased inflammatory cytokines TNF-α, IL-6, IL-10, IFN-γ, CXCL1/2, and fibrosis markers TGF-β1 and MMP-13. In comparison with the FDA-approved drugs Nintedanib and Pirfenidone, RP-832c exhibited a similar reduction in fibrosis compared to Pirfenidone, and to a greater extent than Nintedanib, with no apparent toxicities observed. In summary, our findings showed that inhibiting the profibrotic alternatively activated M2-like macrophages using a novel peptide, RP-832c, could reduce BLM-induced pulmonary fibrosis in mice, warranting the therapeutic potential of this peptide for patients with pulmonary fibrosis.

Keywords
CD206; IPF; immunotherapy; macrophages; myofibroblasts.
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