A Study of the Immunoregulatory Function of TLR3 and TLR4 on Mesenchymal Stem Cells in Ankylosing Spondylitis

摘要

The pathogenesis of ankylosing spondylitis (AS), an immune-mediated inflammatory disease, remains largely unknown. We previously reported that the immunoregulatory function of mesenchymal stem cells (MSCs) was dysfunctional in AS. Furthermore, it has been demonstrated that TLR3 and TLR4 could regulate the immunoregulatory function of MSCs. Therefore, this study aimed to investigate the effect of TLR3 and TLR4 activation on the immunoregulatory function of AS-MSCs. By gene expression and western blot analyses, we found that both TLR3 and TLR4 in AS-MSCs to be downregulated when compared with MSCs derived from healthy donors (HDs). Despite the lower basal expression of TLRs, AS-MSCs were as sensitive or more sensitive to TLR agonists as compared with HD-MSCs in terms of activation of p38 and ERK MAPK signaling pathways. Furthermore, TLR4-primed AS-MSCs were observed to possess enhanced immunoregulatory effects against the proliferation of naive CD4(+) T cells than HD-MSCs due to elevated IL-10 production. However, TLR activation or the source of MSCs did not affect MSC-induced differentiation of naive CD4(+) T cells to Th17 cells. Similarly, the MSC-induced inhibition of Treg cell differentiation of naive CD4(+) T cells was not affected by TLR activation or MSC source. MSC-induced Th17 differentiation was likely mediated by the elevated secretion of proinflammatory cytokines, IL-6 and IL-17, and reduced expression of IL-2, IL-4, and IFN-gamma, which were not affected by TLR activation. Taken together, our results suggest that TLR3 and TLR4 may play an important role in the immunoregulatory function of MSCs in AS patients.