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

Abstract

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 TNF-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. Summary statementPlatelet DKK1 produced in response to TLR1/2 signaling by Leishmania parasites drives development of non-healing responses. In vivo/ in vitro analyses indicate that the mechanism underlying this process is the promotion of tolerogenic dendritic cells, driving Th2 and Th1-IL-10 T cell responses. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/656395v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@5b7049org.highwire.dtl.DTLVardef@128e273org.highwire.dtl.DTLVardef@12af4d2org.highwire.dtl.DTLVardef@12f10d2_HPS_FORMAT_FIGEXP M_FIG C_FIG