GSE64844
IL-10 production and metabolic regulation in macrophages are linked by a TLR-driven CREB-mediated mechanism
IL-10 is produced by macrophages in diverse immune settings and is critical in limiting immune-mediated pathology. In helminth infections macrophages are an important source of IL-10, however the molecular mechanism underpinning production of IL-10 by these cells is poorly characterized. Here, bone marrow derived macrophages exposed to Excretory/Secretory (E/S) products released by Schistosoma mansoni cercariae rapidly produce IL-10 as a result of MyD88-mediated activation of MEK/ERK/RSK and p38. The phosphorylation of these kinases was triggered by TLR2 and TLR4 and converged on activation of the transcription factor CREB. Uptake of cercarial E/S products by phagocytosis was critical for the production of IL-10 and the activation of MAPKs and CREB, which indicates that interactions between E/S products with TLR2 and TLR4, may be occurring in endosomes. Following phosphorylation, CREB is recruited to a novel regulatory element in the Il10 promoter and is also responsible for regulating a network of genes involved in metabolic processes, such as glycolysis, the tricarboxylic acid cycle and oxidative phosphorylation. Moreover, skin resident tissue macrophages, which encounter S. mansoni E/S products during infection, are the first monocytes to produce IL-10 in vivo early after infection with S. mansoni cercariae. The early and rapid release of IL-10 by these cells has the potential to condition the dermal microenvironment encountered by immune cells recruited to this infection site. To conclude, we propose a mechanism by which CREB regulates the production of IL-10 by macrophages in the skin, but also has a major effect on their metabolic state. Overall design: CREB binding sites 3 pooled samples of stimulated bone marrow macrophages