title: MicroRNA 21 is a homeostatic regulator of macrophage polarization and prevents prostaglandin E2-mediated M2 generation.
abstract: Macrophages dictate both initiation and resolution of inflammation. During acute inflammation classically activated macrophages (M1) predominate, and during the resolution phase alternative macrophages (M2) are dominant. The molecular mechanisms involved in macrophage polarization are understudied. MicroRNAs are differentially expressed in M1 and M2 macrophages that influence macrophage polarization. We identified a role of miR-21 in macrophage polarization, and found that cross-talk between miR-21 and the lipid mediator prostaglandin E2 (PGE2) is a determining factor in macrophage polarization. miR-21 inhibition impairs expression of M2 signature genes but not M1 genes. PGE2 and its downstream effectors PKA and Epac inhibit miR-21 expression and enhance expression of M2 genes, and this effect is more pronounced in miR-21-/- cells. Among potential targets involved in macrophage polarization, we found that STAT3 and SOCS1 were enhanced in miR-21-/- cells and further enhanced by PGE2. We found that STAT3 was a direct target of miR-21 in macrophages. Silencing the STAT3 gene abolished PGE2-mediated expression of M2 genes in miR-21-/- macrophages. These data shed light on the molecular brakes involved in homeostatic macrophage polarization and suggest new therapeutic strategies to prevent inflammatory responses.
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Brandt
authors.affiliation: Departamento de Ciências Biológicas, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista "Júlio de Mesquita Filho," 14801-902 Araraquara, São Paulo, Brazil.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Medeiros
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Soujuan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dent
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: C Henrique
authors.initials: CH
authors.lastname: Serezani
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D004917:Erythromycin / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D004917:Erythromycin; C057513:erythromycin propionate-N-acetylcysteinate; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone; D000111:Acetylcysteine