Unknown,Transcriptomics,Genomics,Proteomics

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Myeloid lineage switch in pro-B cells generates novel macrophage subsets during homeostasis and inflammation

ABSTRACT: Here we demonstrate for the first time evidence of lineage switch from B-1 B lymphocyte to a macrophage , or so-called transdifferentiation, occurring in mature cells in vivo. Specifically, using transgenic B6.Mb1-iCre/Rosa26-YFP mice, in which YFP expression is restricted exclusively to B cell lineage, we discovered that a significant portion of tissue-resident macrophages in peritoneum, pleural cavity and intestine in steady state are positive for YFP. B cell origin of YFP+ macrophages was confirmed by next-generation sequencing of genomic DNA locus encoding immunoglobulin heavy chain genes. Eliciting a self-resolving zymosan peritonitis showed that during inflammation a subset of B-1 B cells gives rise to inflammation-induced macrophages. The aim of this study was to perform transcriptome analysis of B-1 B cell-derived macrophages (B-1/macrophages) from the naM-ove and inflamed murine peritoneum and compare them to already established populations of naM-ove tissue-resident macrophages, inflammation-experienced resident (yolk-sac-derived) macrophages and inflammation-induced (monocyte-derived) macrophages.

ORGANISM(S): Mus musculus

SUBMITTER: Dan Frampton

PROVIDER: E-MTAB-1878 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The role of Group IVA cytosolic phospholipase A2 (cPLA2M-NM-1) activation in regulating macrophage transcriptional responses to Candida albicans infection was investigated. cPLA2M-NM-1 releases arachidonic acid for the production of eicosanoids. In mouse resident peritoneal macrophages, prostacyclin, prostaglandin E2 and leukotriene C4 were produced within minutes of C. albicans addition before cyclooxygenase 2 expression. The production of TNFa was lower in C. albicans-stimulated cPLA2a+/+ than cPLA2a-/- macrophages due to an autocrine effect of prostaglandins that increased cAMP to a greater extent in cPLA2a+/+ than cPLA2a-/- macrophages. For global insight, differential gene expression in C. albicans-stimulated cPLA2a+/+ and cPLA2a-/- macrophages (3 h) was compared by microarray. cPLA2M-NM-1+/+ macrophages expressed 86 genes at lower levels and 181 genes at higher levels than cPLA2M-NM-1-/- macrophages (M-bM-^IM-%2-fold, p<0.05 ). Several pro-inflammatory genes were expressed at lower levels (Tnfa, Cx3cl1, Cd40, Ifng, several IFNg-inducible GTPases, Ccl5, Csf1, Edn1, CxCr7, Irf1, Irf4, Akna). Genes that dampen inflammation (Socs3, Il10, Crem, Stat3, Thbd, Thbs1, Abca1) and genes involved in host defense (Gja1, Csf3, Trem1, Hdc) were expressed at higher levels in cPLA2a+/+ macrophages. Representative genes expressed lower in cPLA2a+/+ macrophages (Tnfa and Csf1) were increased by treatment with a prostacyclin receptor antagonist and protein kinase A inhibitor, whereas genes expressed at higher levels (Crem, Nr4a2, Il10, Csf3) were suppressed. The results suggest that C. albicans stimulates an autocrine loop in macrophages involving cPLA2a, cyclooxygenase 1-derived prostaglandins and increased cAMP that globally effects expression of genes involved in host defense and inflammation. Resident peritoneal macrophages from Group IVA cytosolic phospholipase A2 (cPLA2a) +/+ and -/- mice were stimulated with Candida albicans (m.o.i. 2) for 3 hours and RNA isolated to evaluate the role of cPLA2a-derived lipid mediators on gene expression. Three independent experiments were analyzed.

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Myeloid lineage switch in pro-B cells generates novel macrophage subsets during homeostasis and inflammation

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