Abstract
Inflammation involves a series of complex biological processes mediated by innate immunity for host defense against pathogen infection. Chronic inflammation is considered to be one of the major causes of serious diseases, including a number of autoimmune/inflammatory diseases, cancers, cardiovascular diseases, and neurological diseases. Milk fat globule-epidermal growth factor 8 (MFG-E8) is a secreted protein found in vertebrates and was initially discovered as a critical component of the milk fat globule. Previously, a number of studies have reported that MFG-E8 contributes to various biological functions including the phagocytic removal of damaged and apoptotic cells from tissues, the induction of VEGF-mediated neovascularization, the maintenance of intestinal epithelial homeostasis, and the promotion of mucosal healing. Recently, emerging studies have reported that MFG-E8 plays a role in inflammatory responses and inflammatory/autoimmune diseases. This review describes the characteristics of MFG-E8-mediated signaling pathways, summarizes recent findings supporting the roles of MFG-E8 in inflammatory responses and inflammatory/autoimmune diseases, and discusses MFG-E8 targeting as a potential therapeutic strategy for the development of anti-inflammatory/autoimmune disease drugs.
Highlights
Inflammation is the first-line of defense protecting our bodies from harmful stimuli, including pathogen invasion, irritants, and apoptotic or damaged cells [1, 2]
Once macrophages are activated by inflammatory stimuli, they initiate inflammatory responses and produce inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2), reactive oxygen/nitrogen species (ROS/RNS), and proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 through activating intracellular signaling cascades composed of different types of kinases and transcription factors [7,8,9,10,11,12,13,14,15]
Apoptotic cells phosphatidylserine-binding studies have demonstrated that macrophages are activated and play a crucial role for host defense in inflammatory responses and inflammatory/autoimmune diseases via direct phagocytic engulfment of damaged or apoptotic cells through the formation of macrophage-damaged/apoptotic cell complexes mediated by a “molecular bridge,” such as milk fat globule-epidermal growth factor 8 (MFG-E8)
Summary
Inflammation is the first-line of defense protecting our bodies from harmful stimuli, including pathogen invasion, irritants, and apoptotic or damaged cells [1, 2]. Studies have demonstrated that macrophages are activated and play a crucial role for host defense in inflammatory responses and inflammatory/autoimmune diseases via direct phagocytic engulfment of damaged or apoptotic cells through the formation of macrophage-damaged/apoptotic cell complexes mediated by a “molecular bridge,” such as milk fat globule-epidermal growth factor 8 (MFG-E8). An unknown cDNA sequence and its corresponding protein were first identified in 1990, and its DNA sequences were revealed in mouse mammary epithelial cells [16] This gene was named MFG-E8 because it was highly concentrated in milk fat globules and its amino acid sequences were similar to those of both epidermal growth factor (EGF) and blood coagulation factor V/VIII. We provide a general introduction to MFG-E8 as a mediator of damaged/apoptotic cell clearance and discuss the roles of MFG-E8 in macrophage-mediated inflammatory responses and inflammatory/autoimmune diseases. The aim of this review is to increase the understanding of the roles of MFG-E8 in macrophage-mediated inflammatory responses in order to provide new insights that can aid in the development of anti-inflammatory drugs for the treatment of macrophagemediated inflammatory/autoimmune diseases
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