Comparative transcriptome profile of mouse macrophages treated with the RhoA/Rock pathway inhibitors Y27632, Fingolimod (Gilenya), and Rezurock (Belumosudil, SLx-2119)

by Selleckchem | Jul 07 2023

Macrophages play a crucial role in, the currently uncurable, chronic rejection of transplants. In rodent transplantation models, inhibition of the RhoA/Rock pathway disrupts actin-related functions of macrophages, preventing them from entering the graft, and reducing vessel occlusion, fibrosis, and chronic rejection. Among RhoA/Rock inhibitors that inhibit chronic rejection in mouse transplantation are Y27632, Fingolimod, and Rezurock. In a mouse model, Rezurok is more effective in preventing fibrosis and less effective in preventing vessel occlusion than Y27632 or Fingolimod. Fingolimod is FDA-approved for treating multiple sclerosis (MS) and Rezurock for chronic graft versus host disease (GVHD). Still, none had been tested for chronic rejection in humans. To explain the differences in the anti-chronic rejection properties of Y27632, Fingolimod, and Rezurock, we compared the transcriptome profile of mouse macrophages treated with these compounds separately. Treatment with Y27632 or Fingolimod downregulated GTPase and actin pathways involved in cell migration. Rezurock downregulated genes related to fibrosis, such as PTX3, CCR2, CCL2, cell cycle, DNA replication, adaptive immune response, and organelle assembly, while Fingolimod also specifically downregulated NOTCH1 at mRNA . The result of this study not only uncovers which pathways are shared or specific for these drugs but will help in the development of macrophage pathway-targeted therapies in human transplantation, MS, and GVHD. Because macrophages are the major players in immune response, tissue regeneration, renewal, and homeostasis, and development of many diseases, including cancer, the data compiled here will help in designing novel or improved therapies in many clinical applications.

Comments:

Macrophages are a type of immune cell that plays a crucial role in various physiological processes and disease conditions, including transplant rejection. In chronic rejection of transplants, macrophages infiltrate the graft and contribute to vessel occlusion, fibrosis, and the overall rejection process. In rodent transplantation models, inhibition of the RhoA/Rock pathway has shown promise in disrupting the actin-related functions of macrophages, preventing their entry into the graft, and reducing the occurrence of vessel occlusion, fibrosis, and chronic rejection.

Several RhoA/Rock inhibitors have been investigated in mouse transplantation models, including Y27632, Fingolimod, and Rezurock. While Y27632, Fingolimod, and Rezurock have demonstrated efficacy in inhibiting chronic rejection in mice, their specific effects and mechanisms of action may differ. In a mouse model, it has been observed that Rezurock is more effective in preventing fibrosis but less effective in preventing vessel occlusion compared to Y27632 or Fingolimod.

To gain insights into the differences in the anti-chronic rejection properties of these compounds, researchers conducted a transcriptome profiling study using mouse macrophages treated with each inhibitor separately. The transcriptome profile refers to the set of all RNA molecules transcribed in a particular cell or tissue at a given time, providing valuable information about gene expression patterns and cellular functions.

The results of the study revealed distinct effects of Y27632, Fingolimod, and Rezurock on the transcriptome of macrophages. Treatment with Y27632 or Fingolimod downregulated genes associated with GTPase and actin pathways involved in cell migration, which likely contributes to their ability to prevent macrophage infiltration into the graft. Rezurock, on the other hand, downregulated genes involved in fibrosis, such as PTX3, CCR2, and CCL2, as well as genes related to cell cycle, DNA replication, adaptive immune response, and organelle assembly. Interestingly, Fingolimod specifically downregulated the NOTCH1 gene at the mRNA level.

By comparing the transcriptome profiles of macrophages treated with these inhibitors, this study provides valuable insights into the shared and specific pathways targeted by Y27632, Fingolimod, and Rezurock. This information is not only relevant for understanding the mechanisms of action of these drugs in the context of chronic rejection but also holds potential for the development of macrophage pathway-targeted therapies in human transplantation, multiple sclerosis (MS), graft-versus-host disease (GVHD), and other diseases where macrophages play a significant role.

Given the central role of macrophages in immune response, tissue regeneration, renewal, and the development of various diseases, including cancer, the data compiled in this study can be instrumental in designing novel or improved therapies for a wide range of clinical applications. However, it's important to note that further research and clinical trials would be needed to validate the efficacy and safety of these RhoA/Rock inhibitors in human patients with chronic rejection or other relevant conditions.