Immunomodulation by platelet-derived DKK1: potential for controlling disease and pathology in leishmaniasis and...

Parasitic infection caused by Leishmania major in BALB/c mice is a well-established example of a chronic inflammatory disease. Although chronic inflammation in parasitic infections stems from persistent interactions between parasites and host immune cells, the mechanisms by which parasitic infections induce and regulate chronic immune responses remain to be fully understood. Emerging evidence suggests that platelets contribute not only to hemostasis but also modulate immune response during infection and inflammation. This review examines the emerging role of platelet-derived Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, in shaping immunity during cutaneous leishmaniasis and explores its broader implications in other infectious diseases. Experimental findings from BALB/c mouse models indicate that Leishmania major infection promotes platelet activation and DKK1 release, leading to enhanced leukocyte-platelet aggregation and recruitment of neutrophils, macrophages, and dendritic cells to inflammatory sites. Platelet-derived DKK1 appears to influence dendritic cell polarization, favoring cDC2 and DC-10-mediated T-cell differentiation associated with Th2 and regulatory immune responses which contribute to M2 macrophage polarization and intracellular parasite survival. In contrast, protective antileishmanial Th1-associated responses may be diminished in the presence of sustained DKK1 signaling. Thus, this review integrates current evidence indicating that platelet-derived DKK1 functions as an early regulator of both innate and adaptive immune responses during Leishmania infection. Beyond leishmaniasis, accumulating evidence suggests that platelet activation and DKK1 release may also participate in the immunopathology of fungal and viral infections. By integrating current evidence on platelet-mediated immune regulation, this review highlights platelet-derived DKK1 as a potential immunomodulatory target and emphasizes the need for further studies to clarify its translational relevance across infectious diseases.