Platelet-derived DKK1 modulates immune responses in leishmaniasis, influencing Th2 and M2 macrophage polarization.

Understanding the mechanisms behind chronic inflammation in parasitic infections like leishmaniasis is crucial, as current treatments often fall short in fully resolving the complex immune dysregulation. While parasites directly interact with host immune cells, the full scope of how these interactions induce and regulate chronic immune responses remains unclear. Emerging evidence highlights platelets as significant modulators of immunity beyond their traditional role in hemostasis, suggesting they play a critical, yet underappreciated, role in inflammatory and infectious diseases.

This review synthesizes current experimental findings, primarily from BALB/c mouse models of Leishmania major infection, to elucidate the role of platelet-derived Dickkopf-1 (DKK1). The authors examined how Leishmania major infection promotes platelet activation and subsequent DKK1 release, and the downstream effects on immune cell recruitment and polarization. The review integrates evidence on DKK1's influence on Wnt signaling and its impact on both innate and adaptive immune responses during infection, extending its implications to other fungal and viral infections.

Platelet activation and DKK1 release are significantly promoted by Leishmania major infection in BALB/c mouse models. This leads to enhanced leukocyte-platelet aggregation and increased recruitment of neutrophils, macrophages, and dendritic cells to inflammatory sites. Platelet-derived DKK1 specifically influences dendritic cell polarization, favoring cDC2 and DC-10-mediated T-cell differentiation. This differentiation is associated with Th2 and regulatory immune responses, which in turn contribute to M2 macrophage polarization and ultimately, intracellular parasite survival. Conversely, protective antileishmanial Th1-associated responses appear to be diminished in the presence of sustained DKK1 signaling. The review highlights DKK1 as an early regulator of both innate and adaptive immunity.

Beyond leishmaniasis, accumulating evidence suggests that platelet activation and DKK1 release also participate in the immunopathology of fungal and viral infections, indicating a broader role in infectious disease.