Platelet DKK1 promotes tolerogenic dendritic cells and non-healing responses in cutaneous leishmaniasis.

Dickkopf-1(DKK1) is a classical Wnt antagonist, which is released at the initiation of Leishmania major infection through platelet TLR1/2 activation. Using BALB/c mice deficient in platelet MyD88 (MyD88PKO) or platelet DKK1 (DKK1PKO), we assessed whether the transmission of activation signals through MyD88 and subsequent release of DKK1 are critical in regulating the immune response to L. major. At the site of infection, the levels of neutrophil platelet aggregates and activated neutrophils of MyD88(PKO) and DKK1(PKO) mice were reduced. Further, these mice mounted anti-leishmanial Th1-responses and failed to develop progressive lesions. In contrast, WT BALB/c-infected mice developed progressive disease associated with elevated IL-10-producing Th1 and Th2 T cells. Further, elevated CD206+ M2 macrophages and tolerogenic DC-10 cells, which favor parasite proliferation, were observed. In vitro, DKK1 promoted DC IL-10 production and blocked TNFα-induction of IL-12. Overall, these results indicate that platelet-DKK1 promotes disease progression through the induction of tolerogenic DCs and subsequent pathological Th2 and IL-10-Th1 T cell-responses.