Spleen tyrosine kinase aggravates intestinal inflammation through regulating inflammatory responses of macrophage in ulcerative colitis.

Background: Ulcerative colitis (UC) is a persistent chronic, non-specific inflammatory disease, and macrophages play a crucial role in its pathogenesis. Spleen tyrosine kinase (Syk) is strongly associated with the pathogenesis of several inflammatory diseases. However, the role of Syk in the pathogenesis of UC is still obscure.

Methods: Syk expression was analyzed in peripheral blood mononuclear cells (PBMCs) and colonic tissues of UC patients using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunofluorescence. A public database was used to analyze the expression of selected signature genes of interest in UC patients with different expressions of Syk. R788, a small molecule inhibitor of Syk, was used to treat macrophages from mice. The functions of macrophages were assessed using qRT-PCR, flow cytometry, and fluorescence microscopy. Dextran sodium sulfate (DSS)-induced colitis mice model was established to determine the role of Syk in UC.

Results: The Syk levels were markedly increased in PBMCs, colonic tissues, and colonic mucosa lamina propria macrophages from UC patients, and positively related to disease activity. Inhibition of Syk with R788 decreased pro-inflammatory genes expression and increased anti-inflammatory genes expression in peritoneal macrophages and bone marrow macrophages. Blockade of Syk enhanced phagocytosis and bactericidal ability of macrophages. Syk promoted the production of reactive oxygen species of macrophages and M1-type macrophage polarization. Furthermore, inhibition of Syk alleviated intestinal mucosal inflammation in DSS-induced colitis model.

Conclusions: Syk plays a vital role in intestinal inflammation by regulating inflammatory responses of macrophages in UC. Targeting Syk may be a promising therapeutic approach for UC.