The role of the Syk tyrosine-kinase in immune complex-mediated autoimmune inflammation
Kálmán Eszter Gertrúd
Molecular Medicine Division
Dr. Várnai Péter
SE Élettani Intézet könyvtára
2025-12-09 14:00:00
Experimental and clinical immunology and rheumatology
Dr. Mócsai Attila
Dr. Németh Tamás
Dr. Tőke Judit
Dr. Minier Tünde
Dr. Prohászka Zoltán
Dr. Ledó Nóra
Dr. Bodoki Levente
Dr. Tóth Balázs
Syk is a non-receptor tyrosine-kinase, which is an important component of Fcg receptor or b2-integrin signalling. It has been shown that the absence of Syk from the hematopoietic compartment resulted in a total protection from the development of experimental arthritis. This result with further observations raised the possibility to test the effect of Syk-selective inhibition in autoantibody-induced experimental arthritis.
In our experiments, we investigated the effect of a Syk-selective inhibitor (namely entospletinib) in autoantibody-induced experimental arthritis and in in vitro immune-complex and integrin-mediated cell responses of mouse and human neutrophils.
Experimental arthritis was induced by intraperitoneal injection of K/BxN serum. Entospletinib or vehicle were administered orally twice a day. Arthritis was followed by clinical scoring and ankle thickness measurements. The local cytokine levels were detected by ELISA, while the local cell recruitment, synovial fibroblast numbers and the activation status were detected by flow cytometry. In our in vitro experiments, immune-complex- or integrin-triggered neutrophil superoxide release was measured by a cytochrome c-reduction assay, cell spreading was detected by phase contrast microscopy and cytokine production was followed by ELISA.
The oral administration of entospletinib decreased the severity of experimental arthritis. In line with this, the number of synovial neutrophils, the MHC II expression of synovial fibroblasts and the synovial cytokine levels were decreased in the entospletinib-treated group. In line with these findings, entospletinib reduced the immune complex- and integrin-triggered mouse neutrophil cell responses in a dose-dependent manner. Furthermore, entospletinib and lanraplenib dose-dependently decreased the investigated human neutrophil effector responses.
The Syk-selective inhibitor entospletinib could reduce joint inflammation in experimental arthritis, while the tested inhibitors effectively reduced the in vitro investigated neutrophil effector cell responses. Our data raise the possibility that entospletinib (or lanraplenib) could be good drug candidates in the treatment of human autoimmune arthritis.
