Perilla extract potentiates efferocytosis by macrophages: Implications for resolution of inflammation

Abstract

Perilla frutescens (Lamiaceae) have strong anti-inflammatory as well as antioxidant, antimicrobial, anti-allergic, antidepressant, anticancer, and neuroprotective effects and hence have diverse therapeutic applications. We have previously reported that oral administration of the standardized perilla extract ameliorated the experimentally induced colitis in mice by blocking the activation of two prototypic pro-inflammatory transcription factors, NF-κB and STAT3. Upon inflammatory insult, tissue resident macrophages produce vasoactive and chemotactic mediators, which increase vascular permeability and promote the infiltration of leukocytes, especially neutrophils, into the inflamed site where they eliminate or neutralize invading molecules. Neutrophils at the inflamed site undergo apoptosis, and apoptotic cells are removed by macrophages through phagocytosis, a process termed ‘efferocytosis’. This terminates the inflammatory responses. If resolution of inflammation fails, inflammation response becomes excessive and prolonged which can cause tissue damage and loss of the function implicated in pathogenesis of a broad spectrum of human disorders. Here, we report that the standardized leaf extract of P. frutescens potentiated the efferocytic activity of macrophages in a zymosan-induced peritonitis model, which appears to be mediated via the PPARγ activation. We also validated the stimulatory effects of the perilla extract on efferocytosis by isolated peritoneal and bone marrow derived macrophages cocultured with apoptotic cells.