Helminthic dehydrogenase drives PGE(2) and IL‐10 production in monocytes to potentiate Treg induction

Immunoregulation of inflammatory, infection‐triggered processes in the brain constitutes a central mechanism to control devastating disease manifestations such as epilepsy. Observational studies implicate the viability of Taenia solium cysts as key factor determining severity of neurocysticercosis (NCC), the most common cause of epilepsy, especially in children, in Sub‐Saharan Africa. Viable, in contrast to decaying, cysts mostly remain clinically silent by yet unknown mechanisms, potentially involving Tregs in controlling inflammation. Here, we show that glutamate dehydrogenase from viable cysts instructs tolerogenic monocytes to release IL‐10 and the lipid mediator PGE(2). These act in concert, converting naive CD4(+) T cells into CD127(−)CD25(hi)FoxP3(+)CTLA‐4(+) Tregs, through the G protein‐coupled receptors EP2 and EP4 and the IL‐10 receptor. Moreover, while viable cyst products strongly upregulate IL‐10 and PGE(2) transcription in microglia, intravesicular fluid, released during cyst decay, induces pro‐inflammatory microglia and TGF‐β as potential drivers of epilepsy. Inhibition of PGE(2) synthesis and IL‐10 signaling prevents Treg induction by viable cyst products. Harnessing the PGE(2)‐IL‐10 axis and targeting TGF‐ß signaling may offer an important therapeutic strategy in inflammatory epilepsy and NCC.