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

Activation of platelet TLR1/2 at the initiation of Leishmania major infection results in the release of the Wnt antagonist Dickkopf-1 (DKK1). To examine the role of platelet MyD88 and/or DKK1 in regulating the immune response, genetic approaches using BALB/c mice deficient in platelet MyD88 (MyD88PKO) or DKK1 (DKK1PKO) were used. Genetically deficient mice exhibit significant changes in the immune response throughout infection. Initially, the levels of activated neutrophils and neutrophil-platelet aggregates were reduced at the site of infection. Subsequently, an anti-leishmanial Th1-response was observed in these mice, which in contrast to their WT counterparts, fail to develop progressive lesions. Further, WT mice developed comparatively elevated levels of CD206+ M2 macrophages and tolerogenic DC-10 cells. Previously, Chae et al. showed that DKK1 promoted type 2 immunity during Leishmania infection. The current study extends the prior study and demonstrates that DKK1 directly regulates both Th2 and IL-10-Th1 responses by inducing regulatory, tolerogenic DC-10 cells.