Milk Fat Globule-Epidermal Growth Factor 8 (MFG-E8) Is a Novel Anti-inflammatory Factor in Rheumatoid Arthritis in Mice and Humans

Abstract

Milk fat globule-epidermal growth factor 8 (MFG-E8) is an anti-inflammatory glycoprotein that mediates the clearance of apoptotic cells and is implicated in the pathogenesis of autoimmune and inflammatory diseases. Because MFG-E8 also controls bone metabolism, we investigated its role in rheumatoid arthritis (RA), focusing on inflammation and joint destruction. The regulation of MFG-E8 by inflammation was assessed in vitro using osteoblasts, in arthritic mice and in patients with RA. K/BxN serum transfer arthritis (STA) was applied to MFG-E8 knock-out mice to assess its role in the pathogenesis of arthritis. Stimulation of osteoblasts with lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-a downregulated the expression of MFG-E8 by 30% to 35%. MFG-E8-deficient osteoblasts responded to LPS with a stronger production of pro-inflammatory cytokines. In vivo, MFG-E8 mRNA levels were 52% lower in the paws of collagen-induced arthritic (CIA) mice and 24% to 42% lower in the serum of arthritic mice using two different arthritis models (CIA and STA). Similarly, patients with RA (n ¼ 93) had lower serum concentrations of MFG-E8

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

“…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.…”

“…They could further show that the MFG-E8 expression in osteogenic stromal cells, which greatly contribute to the inflammatory bone loss, 42 is downregulated by LPS and TNFa. 5 This means that MFG-E8 not only regulates the inflammatory response but is also regulated by inflammatory stimuli itself 17 (Figure 1). With respect to arthritis, in which regulatory T cells have a crucial role, it is particularly interesting to notice that MFG-E8 has been implicated to control the release of TGF-b and CC chemokine ligand 22, which are both known to attract and maintain the regulatory T-cell phenotype.…”

“…In fact, current studies highlighted an important function of MFG-E8 in the maintenance of proper bone remodeling, as well as in the homeostasis of reproductive organs, epidermal tissue and blood. [4][5][6][7][8] In addition to the regulation of tissue homeostasis, MFG-E8 has been shown to modulate immune reactions. Especially in models of sepsis and ischemia-reperfusion (I/R) injury but also in chronic inflammatory disease models, the expression of MFG-E8 is decreased in affected tissues, leading to a stronger inflammatory response.…”

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“…The serum level of MFG-E8 was found to be higher in SLE patients as compared to very low level in healthy controls [18]. But patients with rheumatoid arthritis showed lower serum concentrations of MFG-E8 compared with healthy controls [9]. It was reported that administration of recombinant MFG-E8 suppressed the ischemia-reperfusion induced inflammation in mouse [19].…”

“…Milk Fat Globule Epidermal Growth Factor-8 (MFG-E8), a novel endometrial epithelial protein, found to have multiple biological functions against inflammation [6,7]. MFG-E8 binds to apoptotic cells, enhances the phagocytosis of apoptotic cells by macrophages and provides an anti-inflammatory function [8,9]. Topical recombinant MFG-E8 treatment induces resolution of wound inflammation, and improvement in angiogenesis [10].…”