Cutaneous leishmaniasis is regulated by Wnt antagonist Dkk-1 from activated platelets (MPF7P.715)

Abstract

Abstract Cutaneous leishmaniasis is a chronic non-healing skin inflammatory disease present in many countries. Here we show that the Wnt antagonist Dkk-1 is secreted from activated platelets and regulates chronic inflammation to Leishmania (L.) major. We found that L. major infection could rapidly elevate circulating levels of Dkk-1. First, Dkk-1 from activated platelets increased neutrophil-platelet aggregate formation mainly via PSGL-1. Second, the continuously high level of Dkk-1 further directed T cell differentiation into Th2 cells in the draining lymph nodes. Secretion of Dkk-1 was regulated by PKC-alpha and GSK3-beta in human platelets upon soluble leishmania antigen exposure in vitro. Functional inhibition of Dkk-1 using a small molecule inhibitor showed marked inhibition of neutrophil-platelet aggregate formation at early hours of infection and also resulted in decreased parasite burden and amelioration of skin lesions after 6 weeks. In vitro studies demonstrate that Th2 skewing is directed by Dkk-1 via p38 and SGK-1 resulting in elevation of GATA-3 and c-Maf. This coordinated expression of two Th2 cytokine transcription factors resulted in robust production of Th2 cytokines (e.g., IL-4, IL-5, IL-10 and IL-13). Thus, our results demonstrate that platelet-derived Dkk-1 regulates early and late inflammatory responses in cutaneous leishmaniasis.