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The biology of nematode- and IL4R?-dependent murine macrophage polarization in vivo as defined by RNA-Seq and targeted lipidomics.

ABSTRACT: Alternatively activated macrophages (AAM?) are a major component of the response to helminth infection; however, their functions remain poorly defined. To better understand the helminth-induced AAM? phenotype, we performed a systems-level analysis of in vivo derived AAM? using an established mouse model. With next-generation RNA sequencing, we characterized the transcriptomes of peritoneal macrophages from BALB/c and IL4R?(-/-) mice elicited by the nematode Brugia malayi, or via intraperitoneal thioglycollate injection. We defined expression profiles of AAM?-associated cytokines, chemokines, and their receptors, providing evidence that AAM? contribute toward recruitment and maintenance of eosinophilia. Pathway analysis highlighted complement as a potential AAM?-effector function. Up-regulated mitochondrial genes support in vitro evidence associating mitochondrial metabolism with alternative activation. We mapped macrophage transcription start sites, defining over-represented cis-regulatory motifs within AAM?-associated promoters. These included the binding site for PPAR transcription factors, which maintain mitochondrial metabolism. Surprisingly PPAR?, implicated in the maintenance of AAM?, was down-regulated on infection. PPAR? expression, however, was maintained. To explain how PPAR-mediated transcriptional activation could be maintained, we used lipidomics to quantify AAM?-derived eicosanoids, potential PPAR ligands. We identified the PPAR? ligand PGI(2) as the most abundant AAM?-derived eicosanoid and propose a PGI(2)-PPAR? axis maintains AAM? during B malayi implantation.

SUBMITTER: Thomas GD

PROVIDER: S-EPMC4314526 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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The biology of nematode- and IL4Rα-dependent murine macrophage polarization in vivo as defined by RNA-Seq and targeted lipidomics.

Thomas Graham D GD Rückerl Dominik D Maskrey Benjamin H BH Whitfield Phillip D PD Blaxter Mark L ML Allen Judith E JE

Blood 20121016 25

Alternatively activated macrophages (AAMϕ) are a major component of the response to helminth infection; however, their functions remain poorly defined. To better understand the helminth-induced AAMϕ phenotype, we performed a systems-level analysis of in vivo derived AAMϕ using an established mouse model. With next-generation RNA sequencing, we characterized the transcriptomes of peritoneal macrophages from BALB/c and IL4Rα(-/-) mice elicited by the nematode Brugia malayi, or via intraperitoneal ...[more]

PMID: 23074280

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Project description:The role of resolvins in abdominal aortic aneurysm (AAA) has not been established. We hypothesized that treatment with D-series resolvins (RvD2 or RvD1) would attenuate murine AAA formation through alterations in macrophage polarization and cytokine expression. Male C57/B6 mice (n = 9 per group) 8 to 12 wk old received RvD2 (100 ng/kg/treatment), RvD1 (100 ng/kg/treatment), or vehicle only every third day beginning 3 d before abdominal aortic perfusion with elastase as prevention. Aortas were collected 14 d after elastase perfusion. Cytokine analysis (n = 5 per group) or confocal microscopy (n = 4 per group) was performed. In a separate experiment, RvD2 was provided to mice with small AAAs 3 d after elastase treatment (n = 8 per group). Additionally, apolipoprotein E knockout mice treated with angiotensin II (1000 ng/kg) were treated with RvD2 or vehicle alone (n = 10 per group) in a nonsurgical model of AAA. To determine the effect of RvD2 on macrophage polarization, confocal staining for macrophages, M1 and M2 macrophage subtypes, α-actin, and DAPI was performed. Mean aortic dilation was 96 ± 13% for vehicle-treated mice, 57 ± 9.7% for RvD2-treated mice, and 61 ± 11% for RvD1-treated mice (P < 0.0001). Proinflammatory cytokines macrophage chemotactic protein 1, C-X-C motif ligand 1, and IL-1β were significantly elevated in control animals compared to RvD2- and RvD1-treated animals (P < 0.05), resulting in a reduction of matrix metalloproteinase 2 and 9 activity in resolvin-treated mice in both elastase and angiotensin II models. Treatment of existing small AAAs with RvD2 demonstrated a 25% reduction in aneurysm size at d 14 compared to vehicle alone (P = 0.018). Confocal histology demonstrated a prevalence of M2 macrophages within the aortic medium in mice treated with RvD2. Resolvin D2 exhibits a potent protective effect against experimental AAA formation. Treatment with RvD2 significantly influences macrophage polarization and decreases several important proinflammatory cytokines. Resolvins and the alteration of macrophage polarization represent potential future targets for prevention of AAA.-Pope, N. H., Salmon, M., Davis, J. P., Chatterjee, A., Su, G., Conte, M. S., Ailawadi, G., Upchurch, G. R., Jr. D-series resolvins inhibit murine abdominal aortic aneurysm formation and increase M2 macrophage polarization.

Dataset Information

The biology of nematode- and IL4R?-dependent murine macrophage polarization in vivo as defined by RNA-Seq and targeted lipidomics.

Publications

The biology of nematode- and IL4Rα-dependent murine macrophage polarization in vivo as defined by RNA-Seq and targeted lipidomics.

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