부산대학교 도서관

Macrophages have a defined role in the pathogenesis of metabolic disease and cholesterol metabolism where alternative activation of macrophages is thought to be beneficial to both glucose and cholesterol metabolism during high fat diet induced disease. It is well established that helminth infection protects from metabolic disease, but the mechanisms underlying protection are not well understood. Here, we investigated the effects of Schistosoma mansoni infection and cytokine activation in the metabolic signatures of bone marrow derived macrophages using an approach that integrated transcriptomics, metabolomics, and lipidomics in a metabolic disease prone mouse model. We demonstrate that bone marrow derived macrophages (BMDM) from S. mansoni infected male ApoE-/- mice have dramatically increased mitochondrial respiration compared to those from uninfected mice. This change is associated with increased glucose and palmitate shuttling into TCA cycle intermediates, increased accumulation of free fatty acids, and decreased accumulation of cellular cholesterol esters, tri and diglycerides, and dependent on mgll activity. Systemic injection of IL-4 complexes is unable to recapitulate either reductions in systemic glucose AUC or the re-programing of BMDM mitochondrial respiration seen in infected males. Importantly, the metabolic reprogramming of male myeloid cells is transferrable via bone marrow transplantation to an uninfected host, indicating maintenance of reprogramming in the absence of sustained antigen exposure. Finally, schistosome induced metabolic and bone marrow modulation is sex-dependent, with infection protecting male, but not female mice from glucose intolerance and obesity. Our findings identify a transferable, long-lasting sex-dependent reprograming of the metabolic signature of macrophages by helminth infection, providing key mechanistic insight into the factors regulating the beneficial roles of helminth infection in metabolic disease. Author summary: Globally, helminth endemic regions have lower incidences of metabolic disease. Schistosomiasis in particular has been shown to protect male mice from the development of atherosclerosis, diabetes and obesity while altering the metabolism of liver macrophages. In this study we sought to understand if metabolic modulation occurs systemically. We have found for the first time that macrophages generated from bone marrow myeloid progenitors from infected male mice have long-lived increases in their basal metabolism of lipids. We have also found the type-2 polarizing cytokine is not sufficient to replicate infection induced metabolic reprogramming. Importantly, we demonstrate that the changes to male macrophage metabolism can be transferred to an uninfected host. This suggests that metabolic reprogramming is long-lived without exposure to active infection, and develops a memory-like phenotype in myeloid cells. [ABSTRACT FROM AUTHOR]