INVESTIGATING THE ROLE OF ARHGAP25 IN INFLAMMATORY DISEASES USING MURINE MODELS
Czárán Domonkos Tamás
Molekuláris Orvostudományok
Dr. Várnai Péter
Semmelweis Egyetem Elméleti Orvostudományi Központ Hári Pál Előadóterem
2025-11-05 12:30:00
Celluláris és molekuláris élettan
Dr. Hunyady László
Dr. Csépányi-Kömi Roland
Dr. Papp-Balogh Andrea
Dr. Cervenak László
Dr. Nagy György
Dr. Szabó Györgyi
Dr. Lányi Árpád
Although inflammatory diseases affect many people worldwide, their treatment remains limited and primarily addresses the symptoms rather than the root cause of the disease. For this reason, a deeper understanding of disease mechanisms and the identification of novel therapeutic targets are still highly necessary.
ARHGAP25 is a GTPase-activating protein that regulates the GTP-GDP cycle and thus the activity of the small G protein RAC. Our research group cloned the full-length ARHGAP25 protein and described its role in the regulation of neutrophil effector functions and leukocyte extravasation for the first time. Although initially ARHGAP25 was considered leukocyte-specific, and indeed, the expression level of this GAP is the highest in immune cells, recently, more and more publications have described its role in different types of tumors and tumor cells.
Based on these data, we hypothesized that ARHGAP25 could be a major regulatory component in inflammatory diseases, where the contribution of immune cells is extremely important. Therefore, we aimed to investigate the role of ARHGAP25 in two mechanistically distinct murine disease models of inflammation, the K/BxN serum transfer arthritis and the TNCB-induced allergic contact hypersensitivity model.
Our results demonstrate that the lack of ARHGAP25 mitigates disease severity and symptoms in both cases. In arthritis, reduced edema, pain sensitivity, and loss of articular function are associated with decreased synovial hyperplasia and cartilage destruction. In both models, the absence of ARHGAP25 resulted in decreased leukocyte recruitment and inflammatory cytokine content. During sensitization with the allergen, however, the protein had no effect on T cell homing and activation in the draining lymph nodes. Furthermore, significant ARHGAP25 expression could be detected in fibroblast-like synoviocytes. In contrast, while the expression of ARHGAP25 increased in allergic murine and human samples, it could not be detected in the epidermis. Based on these findings, complemented with our data from bone marrow chimeric mice, we conclude that ARHGAP25 likely regulates inflammation by modulating cytokine production and subsequent leukocyte recruitment. In arthritis, both immune cells and fibroblast-like synoviocytes are regulated by this protein, while in contact hypersensitivity, only cells of hematopoietic origin are affected.
