Schistosoma mansoni infection metabolically reprograms the myeloid lineage in a mouse model of metabolic disease
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ABSTRACT: We studied the effects of helminth 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. 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. Finally, 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. Conclusions: Our findings identify a transferable and long-lasting reprograming of the metabolic signature of macrophages by helminth infection that is sufficient to improve systemic glucose metabolism thus providing a mechanistic insight into the factors regulating the beneficial roles of infection in metabolic disease
Project description:Bone marrow cells were isolated, primed with M-CSF (M-BMDM) or GM-CSF (GM-BMDM) and cultured for 7 days. The proteomic difference between GM-BMDM and M-BMDM were analyzed to describe the phenotye and function of two types of macrophages.
Project description:Despite strong evidence that prior helminth infection exerts a protective effect against the development of metabolic disease, a major gap exists in understanding the mechanism(s) underlying this protection. We previously found that Schistosoma mansoni infection induces dramatic transcriptional alterations in hepatic macrophage metabolism, and that this correlates with protection from high fat diet (HFD) induced atherosclerosis and glucose intolerance in male ApoE-/- mice. We sought in the present study to determine the broad effects of S. mansoni exposure on the myeloid lineage using the ApoE-/- HFD model. We uncovered that macrophages derived from the bone marrow of S. mansoni infected male mice have dramatically increased oxygen consumption and mitochondrial mass compared to those from uninfected mice. This shift is accompanied by increased glucose shuttling into TCA cycle intermediates and decreased cholesterol esters. When we examined the role of biological sex in schistosome induced modulation. We found that S. mansoni infection does not reliably protect ApoE-/- female mice from HFD induced weight gain or glucose intolerance. The sex-dependent effect of infection extends to myeloid precursors, where the metabolic phenotype of bone marrow derived macrophages from infected females are the opposite of those from infected males. Overall, these data present the first evidence that S. mansoni systemically modulates the myeloid compartment in a sex-dependent manner.
Project description:murine p16ink4a deficient (p16ko) and control (p16wt) bone marrow cells were either differentiated with normal LCM-supplemented differentiation medium to obtain bone marrow derived macrophages (BMDM) or supplemented with Interleukin 4 during differeniation to obtain M2 polarized p16wt and p16ko BMDM.
Project description:Bone marrow derived macrophages (BMDM) generated from c57bl/6j mice bone marrow cells were stimulated for 18 h with 12 microgram/ml adiponectin, RNA from non-stimulated or 18 h adiponectin-stimulated BMDM subjected to a agilent microarray analysis
Project description:mRNA microarray analysis of bone marrow derived macrophages treated under four conditions, including Naïve (N). Bone marrow derived macrophages (BMDM) were derived from the bone marrow of mice and cultured in the presence of PAO, IFN-gamma, or lipopolysaccharide (LPS). Profiled groups include Naive, LPS, IFN, PAO. Compared each of the groups (PAO, LPS, IFN) with Naïve group.
Project description:We used Illumina sequencing of poly-A selected RNA of Leishmania mexicana (WHO strain MNYC/BZ/62/M379) culture-adapted promastigotes (PRO), axenic amastigotes (AXA) and intracellular amastigotes (AMA) in mouse bone marrow derived macrophages (BMDM), 24h after infection, to map 5' and 3' ends of Leishmania transcripts and determine transcript abundances. The AMA samples were prepared from total RNA of infected macrophages thus containing a mixture of leishmanial and murine RNA transcripts. We also sequenced poly-A selected RNA from uninfected BMDMs. Three biological replicates per sample.
Project description:Bone marrow derived macrophages (BMDM) generated from c57bl/6j mice bone marrow cells were stimulated for 18 h with 12 microgram/ml adiponectin, RNA from non-stimulated or 18 h adiponectin-stimulated BMDM subjected to a agilent microarray analysis Three different non-stimulated and 3 different 18 h adiponectin (12 microgram/ml) RNA samples were subjected to a micrrorray analysis
Project description:mRNA microarray analysis of bone marrow derived macrophages treated under four conditions, including Naïve (N). Bone marrow derived macrophages (BMDM) were derived from the bone marrow of mice and cultured in the presence of PAO, IFN-gamma, or lipopolysaccharide (LPS). Profiled groups include Naive, LPS, IFN, PAO.
Project description:We performed RNA-seq to characterize the transcriptome of tumor-associated macrophages (TAMs), bone marrow-derived monocytes from healthy and tumor-bearing mice (BMDM-Ts/BMDM-Hs) and, macrophages from healthy mammary fat pad (MGMs).