Thrombocytopenia in murine schistosomiasis is associated with platelet uptake by liver macrophages that have a distinct activation phenotype

Alongside their well-established role in hemostasis, platelets are key modulators of immune cell function. This is particularly the case for macrophages, as platelets can either promote or dampen macrophage activation in a context-specific manner. Whilst the role of platelets in modulating classical (M1) macrophage activation following bacterial challenge is relatively well understood, whether platelets control other macrophage responses is less clear. We investigated the role of platelets in type 2 inflammation using a mouse model of chronic schistosomiasis. Schistosome infection caused thrombocytopenia which was not fully reversed after drug-induced parasite death. Reduced platelet levels in infection were coincident with lower levels of systemic TPO and extensive liver damage caused by parasite eggs. Infection also reduced the ploidy and size (but not number) of bone marrow megakaryocytes, which was associated with reduced platelet output. We show schistosome infection accelerated platelet clearance and promoted the formation of platelet-leukocyte aggregates. This was particularly the case for liver macrophages and monocytes. Phenotypic analysis shows that platelet-associated liver macrophages had a distinct activation phenotype that included elevated expression of the alternative (M2) activation marker RELMα. Despite this, in vitro studies indicated that platelets do not directly promote macrophage alternative activation. Similarly, whilst in vivo pharmacological treatment with a TPO mimetic enhanced platelet numbers and platelet-leukocyte aggregates, this did not alter macrophage phenotype. Conversely, antibody-mediated depletion of platelets or use of platelet-deficient mice both led to extensive bleeding following infection which impacted host survival. Together, these data indicate that whilst platelets are essential to prevent excessive disease pathology in schistosomiasis, they have a more nuanced role in myeloid cell activation and type 2 immune responses.