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

Gheberemedhin, A.; Salam, A. B.; Adu-Addai, B.; Noonan, S.; Stratton, R.; Ahmed, M. S. U.; khantwal, C.; Martin, G.; Huixian, L.; Andrews, C.; Balasubramanyam, K.; Udo, R.; Henry, L.; Jaynes, J.; Yates, C.

doi:10.1101/2020.07.27.218115

bioRxiv · 10.1101/2020.07.27.218115

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

Gheberemedhin, A.·Salam, A. B.·Adu-Addai, B.·Noonan, S.·Stratton, R.·Ahmed, M. S. U.·khantwal, C.·Martin, G.·Huixian, L.·Andrews, C.·Balasubramanyam, K.·Udo, R.·Henry, L.·Jaynes, J.·Yates, C.

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Abstract

Activated M2 polarized macrophages are drivers of pulmonary fibrosis in several clinical scenarios such as Acute Respiratory Disease Syndrome (ARDS) and Idiopathic Pulmonary Fibrosis (IPF), through the production of inflammatory and fibrosis-inducing cytokines. In this study, we investigated the effect of targeting the CD206 receptor with a novel fragment of a Host Defense Peptide (HDP), RP-832c to decrease cytokines that cause fibrosis. 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 marker TNF, which resolves over a 24hr period. To elucidate the antifibrotic effect of RP-832c, we used a murine model of bleomycin (BLM) -induced early-stage pulmonary fibrosis. RP-832c significantly reduced bleomycin-induced fibrosis in a dosage dependent manner, as well as decreased CD206, TGF-{beta}1 and -SMA expression in mouse lungs. Interestingly we did not observe any changes in the resident alveolar macrophage marker CD170 expression. Similarly, in an established model of lung fibrosis, RP-832c significantly decreased fibrosis in the lung, as well as significantly decreased inflammatory cytokines TNF, IL-6, IL-10, INF-{gamma}, CXCL1/2, and fibrosis markers TGF-{beta}1 and MMP-13. In comparison with 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 on body weight or blood chemistry. In summary, RP-832c is a potential agent to mitigate the overactivity of M2 macrophages in pathogenesis several pulmonary fibrotic diseases, including SARS-CoV-2 induced lung fibrosis.

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Gheberemedhin, A., Salam, A. B., Adu-Addai, B., Noonan, S., Stratton, R., Ahmed, M. S. U., khantwal, C., Martin, G., Huixian, L., Andrews, C., Balasubramanyam, K., Udo, R., Henry, L., Jaynes, J., Yates, C.. 2020-07-29. A Novel CD206 Targeting Peptide Inhibits Bleomycin Induced Pulmonary Fibrosis in Mice. https://doi.org/10.1101/2020.07.27.218115

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