Fecal bacteria from ulcerative colitis patients downregulate Tim-3-mediated inhibitory effects on monocytes in vitro

Abstract

Tim-3 is highly expressed on monocytes and macrophages. Blocking Tim-3 was shown to promote macrophage activation. We previously showed that fecal bacteria from patients with active ulcerative colitis (UC) presented significantly higher capacity to stimulate monocyte activation, resulting in higher expression of MHC molecules, costimulatory molecules, and proinflammatory cytokines, but the underlying mechanism remained unclear. Here, we found that fecal bacteria could significantly downregulate the expression of Tim-3 on CD14+ classical monocytes in vitro. Compared to the monocytes from healthy individuals, the monocytes from UC patients not only presented lower Tim-3 expression directly ex vivo, but also presented lower Tim-3 expression after stimulation. Moreover, the extent of Tim-3 downregulation was higher in UC monocytes than in control monocytes. This effect was, at least in part, attributable to differences in fecal bacterium composition between UC patients and healthy controls, since when tested in unrelated volunteers, the fecal bacteria from UC patients presented higher capacity at mediating Tim-3 downregulation. Fecal bacteria also induced TNF-α and IL-6 secretion from monocytes, which was repressible by the Tim-3 ligand Galectin 9 (Gal-9). Interestingly, we found that monocytes from UC patients presented significantly reduced response to exogenous Gal-9, and the extent of Gal-9-mediated inhibition was directly correlated with the level of Tim-3 expression. Overall, our data suggested that the monocytes from UC patients presented lower Tim-3 expression and reduced response to exogenous Gal-9, and the fecal bacteria from UC patients could potently downregulate Tim-3 expression on monocytes in vitro.