MFG-E8 Attenuates Intestinal Inflammation in Murine Experimental Colitis by Modulating Osteopontin-Dependent αvβ3 Integrin Signaling

Abstract

MFG-E8 (milk fat globule-epidermal growth factor 8) deficiency is strongly associated with acquisition of immune-mediated disorders due to the loss of tissue homeostasis. However, comparatively little is known regarding its functions in gastrointestinal tract disorders, in which immune homeostasis is a major concern. Herein, we report altered MFG-E8 expression in inflamed colons during the acute phase of murine experimental colitis and found that treatment with recombinant MFG-E8, but not its arginine-glycine-aspartate mutant counterpart, ameliorated colitis by reducing inflammation and improving disease parameters. To reveal the MFG-E8-mediated antiinflammatory mechanism, we employed an in vitro system, which showed the down-regulation of NF-κB in an LPS-dependent manner. Additionally, MFG-E8 altered αvβ3 integrin-mediated focal adhesion kinase phosphorylation by impeding the binding of one of its potent ligands osteopontin, which becomes activated during colitis. Taken together, our results indicated that MFG-E8 has a novel therapeutic potential for treatment of colitis.

Polarization of Prostate Cancer-associated Macrophages Is Induced by Milk Fat Globule-EGF Factor 8 (MFG-E8)-mediated Efferocytosis

“…Deficient efferocytosis is associated with autoimmune diseases because of exacerbated and abnormal inflammatory responses (16,17). Efferocytosis via MFG-E8 influences phagocytic cells such as macrophages and dendritic cells to down-regulate proinflammatory responses (22,43). Furthermore, MFG-E8 has anti-inflammatory roles in homeostasis, evidenced by its modulation of proinflammatory signaling during efferocytosis through activation of the ␣ v ␤ 3 integrin receptors expressed by macrophages (18,43,44).…”

“…Efferocytosis via MFG-E8 influences phagocytic cells such as macrophages and dendritic cells to down-regulate proinflammatory responses (22,43). Furthermore, MFG-E8 has anti-inflammatory roles in homeostasis, evidenced by its modulation of proinflammatory signaling during efferocytosis through activation of the ␣ v ␤ 3 integrin receptors expressed by macrophages (18,43,44). Pretreatment of macrophages with the MFG-E8 recombinant protein resulted in reduced proinflammatory responses induced by LPS stimulation (22).…”

Role of milk fat globule-epidermal growth factor 8 in osteoimmunology

“…In pathophysiological conditions such as sepsis, 34 I/R injury, 35,36 ulcerative colitis 37,38 and atherosclerosis, 39 a significant downregulation of MFG-E8 was reported (Figure 1). For instance, tissue concentrations of MFG-E8 in septic rats have been described to decrease while the number of apoptotic cells increased simultaneously.…”

“…41 Also in a colitis model, MFG-E8 reduced NF-kB signaling and modulated a v b 3 integrin expression. 37 The study of Albus et al, 5 which investigated the role of MFG-E8 in rheumatoid arthritis, further underlines the observation that an inflammatory milieu reduces MFG-E8 levels. Patients suffering from rheumatoid arthritis had lower MFG-E8 serum concentrations compared with healthy controls, which rose again after complete or partial remission.…”

Butyric acid attenuates intestinal inflammation in murine DSS-induced colitis model via milk fat globule-EGF factor 8

“…14,15 We previously found that the anti-inflammatory role of recombinant MFG-E8 protein in DSS-induced colitis was exerted by modulating LPSinduced innate-immune responses in macrophages. 28 Also, Chogle et al 29 demonstrated that MFG-E8KO mice develop more severe crypt-epithelial injury during the onset of DSSinduced acute colitis, 29 whereas a recent study revealed the anti-inflammatory effects of recombinant MFG-E8 protein in a mouse model of ischemia and reperfusion-induced intestinal injuries. 16 Thus, a beneficial effect of MFG-E8 on downregulation of inflammation has been shown.…”