Inhibition of α2,6-sialyltransferase relieves symptoms of ulcerative colitis by regulating Th17 cells polarization

Abstract

Ulcerative colitis (UC) is a chronic, relapsing inflammatory disease that affects human intestines. Immune imbalance is one of the important factors inducing UC. After the activation of CD4⁺ T cells, pro-inflammatory cytokines are produced to induce colonic inflammation. α2,6-Sialylation, catalyzed by α2,6-sialyltransferase (ST6GAL1), affects the proliferation, activation, and T cell receptor (TCR) signaling of CD4⁺ T cells, but its role in CD4⁺ T cell polarization, regulation of Th17 / Treg balance, and its role in UC are still unclear. We found the number of CD4⁺ T and Th17 cells increased in colonic tissue with UC. The level of α2,6-sialylation of CD4⁺ T cells in patients with UC was significantly increased. De-α2,6-sialylation significantly reduced the symptoms of UC in rats. ST6GAL1 gene knockout inhibited the polarization of CD4⁺ T cells to Th17 cells, and promoted the polarization of CD4⁺ T cells to Treg cells. ST6GAL1 knockout significantly inhibited the IL-17 signaling pathway in CD4⁺ T cells and inhibited the secretion of pro-inflammatory cytokine IL-17a. ST6GAL1 and IL-17a are highly expressed in patients with UC, and there is a positive correlation between them. In conclusion, reduced α2,6-sialylation inhibits the polarization of CD4⁺ T cells to Th17 cells, inhibits IL-17a signaling pathway and reduces the level of pro-inflammatory cytokine IL-17a to alleviate the symptoms of UC, which is a potential novel target for the clinical treatment of UC.

Keywords: IL-17a; Polarization; ST6GAL1; Ulcerative colitis; α2,6-sialylation.