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 (MyD88 ^PKO ) or platelet DKK1 (DKK1 ^PKO ), 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.