The biology of nematode- and IL4Rα-dependent murine macrophage polarization in vivo as defined by RNA-Seq and targeted lipidomics.
Blood
; 120(25): e93-e104, 2012 Dec 13.
Article
em En
| MEDLINE
| ID: mdl-23074280
ABSTRACT
Alternatively activated macrophages (AAMÏ) are a major component of the response to helminth infection; however, their functions remain poorly defined. To better understand the helminth-induced AAMÏ phenotype, we performed a systems-level analysis of in vivo derived AAMÏ 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 thioglycollate injection. We defined expression profiles of AAMÏ-associated cytokines, chemokines, and their receptors, providing evidence that AAMÏ contribute toward recruitment and maintenance of eosinophilia. Pathway analysis highlighted complement as a potential AAMÏ-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 AAMÏ-associated promoters. These included the binding site for PPAR transcription factors, which maintain mitochondrial metabolism. Surprisingly PPARγ, implicated in the maintenance of AAMÏ, was down-regulated on infection. PPARδ expression, however, was maintained. To explain how PPAR-mediated transcriptional activation could be maintained, we used lipidomics to quantify AAMÏ-derived eicosanoids, potential PPAR ligands. We identified the PPARδ ligand PGI(2) as the most abundant AAMÏ-derived eicosanoid and propose a PGI(2)-PPARδ axis maintains AAMÏ during B malayi implantation.
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Base de dados:
MEDLINE
Assunto principal:
Brugia Malayi
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Macrófagos Peritoneais
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Receptores de Superfície Celular
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Filariose
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Interações Hospedeiro-Parasita
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article