Biogenesis of Interleukin 10 in Macrophages exposed to Schistosoma mansoni cercarial products

The interaction between antigen presenting cells in the skin with molecules secreted by cercariae of Schistosoma mansoni constitutes the first point of contact between the host’s immune system and the pathogen. High levels of IL-10 are produced in infected skin, and macrophages, which readily take up the molecules secreted by cercariae, are among the first population recruited to the site of infection. Macrophages produce high levels of IL-10 when exposed to cercarial excreted/secreted (E/S) products, as well as other cytokines and chemokines (i.e. IL-1β, IL-6, TNF-α and CCL2), but it is unknown what signalling pathway(s) drive the production of IL-10, rather than other pro-inflammatory cytokines such as IL-12p40, or how they are linked to innate recognition of E/S antigens. Our findings demonstrate that TLRs, particularly TLR4 and TLR2, play a fundamental role in the induction of IL-10. Furthermore, MyD88 is essential for the activation of multiple MAPK pathways which in turn control E/S product-induced IL-10. Selective chemical inhibition of specific pathways allowed us to determine the contribution of each signalling cascade. We established that the activation of MEK/Erk and p38 induced the production of IL-10, whilst it negatively affected IL-12p40. Furthermore, the activation of these kinases leads to the phosphorylation of CREB, which is responsible for the observed effects on IL-10 by being recruited to the promoter of the IL-10 gene. Finally, we show that TLR4 and TLR2 are directly implicated in the activation of these pathways and that macrophages in the skin produce IL-10 as a result of cercarial invasion. From these findings we propose a mechanism by which S. mansoni E/S products induce a specific MAPK signalling cascade that triggers IL-10 production in macrophages by binding their TLRs, thus polarizing the immune response in the skin.