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