title: Engulfment of apoptotic cells by macrophages: a role of microRNA-21 in the resolution of wound inflammation.
abstract: At an injury site, efficient clearance of apoptotic cells by wound macrophages or efferocytosis is a prerequisite for the timely resolution of inflammation. Emerging evidence indicates that microRNA-21 (miR-21) may regulate the inflammatory response. In this work, we sought to elucidate the significance of miR-21 in the regulation of efferocytosis-mediated suppression of innate immune response, a key process implicated in resolving inflammation following injury. An increased expression of inducible miR-21 was noted in postefferocytotic peripheral blood monocyte-derived macrophages. Such induction of miR-21 was associated with silencing of its target genes PTEN and PDCD4. Successful efferocytosis of apoptotic cells by monocyte-derived macrophages resulted in the suppression of LPS-induced NF-κB activation and TNF-α expression. Interestingly, bolstering of miR-21 levels alone, using miR mimic, resulted in significant suppression of LPS-induced TNF-α expression and NF-κB activation. We report that efferocytosis-induced miR-21, by silencing PTEN and GSK3β, tempers the LPS-induced inflammatory response. Macrophage efferocytosis is known to trigger the release of anti-inflammatory cytokine IL-10. This study demonstrates that following successful efferocytosis, miR-21 induction in macrophages silences PDCD4, favoring c-Jun-AP-1 activity, which in turn results in elevated production of anti-inflammatory IL-10. In summary, this work provides direct evidence implicating miRNA in the process of turning on an anti-inflammatory phenotype in the postefferocytotic macrophage. Elevated macrophage miR-21 promotes efferocytosis and silences target genes PTEN and PDCD4, which in turn accounts for a net anti-inflammatory phenotype. Findings of this study highlight the significance of miRs in the resolution of wound inflammation.
authors.affiliation: Department of Surgery, Davis Heart and Lung Research Institute, Center for Regenerative Medicine and Cell Based Therapies and Comprehensive Wound Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210.
authors.forename: Amitava
authors.initials: A
authors.lastname: Das
authors.forename: Kasturi
authors.initials: K
authors.lastname: Ganesh
authors.forename: Savita
authors.initials: S
authors.lastname: Khanna
authors.forename: Chandan K
authors.initials: CK
authors.lastname: Sen
authors.forename: Sashwati
authors.initials: S
authors.lastname: Roy
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D020868:Gene Silencing; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology*; D035683:MicroRNAs / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D010587:Phagocytosis; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014945:Wound Healing / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C508609:IL10 protein, human; D008070:Lipopolysaccharides; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C114487:PDCD4 protein, human; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human