Loss of Protein Kinase D2 Activity Protects Against Bleomycin-Induced Dermal Fibrosis in Mice.

Abstract

Protein kinase D (PKD) has been linked to inflammatory responses in various pathologic conditions; however, its role in inflammation-induced dermal fibrosis has not been evaluated. In this study, we aimed to investigate the roles and mechanisms of protein kinase D2 (PKD2) in inflammation-induced dermal fibrosis and evaluate the therapeutic potential of PKD inhibitors in this disease. Using homozygous kinase-dead PKD2 knock-in (KI) mice, we examined whether genetic ablation or pharmacologic inhibition of PKD2 activity affected dermal inflammation and fibrosis in a bleomycin (BLM)-induced skin fibrosis model. Our data showed that dermal thickness and collagen fibers were significantly reduced in BLM-treated PKD2 KI mice compared with that in wild-type mice, and so was the expression of α-smooth muscle actin and collagens and the mRNA levels of transforming growth factor-β1 and interleukin-6 in the KI mice. Corroboratively, pharmacologic inhibition of PKD by CRT0066101 also significantly blocked BLM-induced dermal fibrosis and reduced α-smooth muscle actin, collagen, and interleukin-6 expression. Further analyses indicated that loss of PKD2 activity significantly blocked BLM-induced infiltration of monocytes/macrophages and neutrophils in the dermis. Moreover, using bone marrow-derived macrophages, we demonstrated that PKD activity was required for cytokine production and migration of macrophages. We have further identified Akt as a major downstream target of PKD2 in the early inflammatory phase of the fibrotic process. Taken together, our findings indicate that PKD2 promotes dermal fibrosis via regulating immune cell infiltration, cytokine production, and downstream activation of Akt in lesional skin, and targeted inhibition of PKD2 may benefit the treatment of this condition.

• Authors: Liping Chen, Jinjun Zhao, Yapeng Chao, Adhiraj Roy, Wenjing Guo, Jiabi Qian, Wanfu Xu, Robyn T Domsic, Robert Lafyatis, Binfeng Lu, Fan Deng, Q Jane Wang
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 103 Issue 2 Pg. 100018 (02 2023) ISSN: 1530-0307 [Electronic] United States
• PMID: 37039152 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Actins
• Bleomycin
• Collagen
• Interleukin-6
• Protein Kinase D2
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Mice
• Actins (genetics, metabolism)
• Bleomycin (toxicity)
• Collagen (metabolism)
• Disease Models, Animal
• Fibrosis
• Inflammation (metabolism)
• Interleukin-6
• Protein Kinase D2 (genetics)
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Scleroderma, Systemic