• Amitava Das, Kasturi Ganesh, Savita Khanna, Chandan K Sen, and Sashwati Roy.
• 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.
• J. Immunol. 2014 Feb 1; 192 (3): 1120-9.

AbstractAt 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.

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