Milk Fat Globule-EGF Factor 8 in Inflammatory Processes

Milk Fat Globule-EGF Factor 8 (MFG-E8), also known as lactadherin, is a secreted glycoprotein that plays a pivotal role in the resolution of inflammation through its function as an opsonin for apoptotic cells. By bridging phosphatidylserine on dying cells to integrin receptors on phagocytes, MFG-E8 facilitates efferocytosis and prevents secondary necrosis. Beyond cell clearance, MFG-E8 influences macrophage phenotype, tipping a balance towards anti-inflammatory programmes and promoting tissue repair. Dysregulation of MFG-E8 has been implicated in a broad spectrum of inflammatory disorders—including sepsis, ischaemia–reperfusion injury, autoimmune diseases, chronic obstructive pulmonary disease and inflammatory bowel diseases—underscoring its global significance. Mechanistic studies have elucidated key signalling pathways, notably the STAT3–SOCS3 axis, by which MFG-E8 temperate proinflammatory cytokine production and promote homeostatic recovery in injured tissues. These insights have catalysed interest in therapeutic strategies aimed at restoring or augmenting MFG-E8 activity in clinical settings.

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Technical terms

Milk Fat Globule-EGF Factor 8 (MFG-E8): A secreted glycoprotein that bridges apoptotic cells and phagocytes, promoting efferocytosis and regulating immune responses.

Efferocytosis: The phagocytic clearance of apoptotic cells, crucial for resolution of inflammation and prevention of secondary necrosis.

Macrophage polarization: The functional reprogramming of macrophages into proinflammatory (M1) or anti-inflammatory (M2) phenotypes.

Signal transducer and activator of transcription 3 (STAT3): A transcription factor activated by phosphorylation that regulates genes involved in anti-inflammatory processes.

Suppressor of cytokine signalling 3 (SOCS3): A negative regulator of cytokine signalling that limits inflammatory pathways by inhibiting JAK–STAT activation.

References

1. Functional Role of Milk Fat Globule‐Epidermal Growth Factor VIII in Macrophage‐Mediated Inflammatory Responses and Inflammatory/Autoimmune Diseases. Mediators of Inflammation (2016).
2. MFG-E8 Released by Apoptotic Endothelial Cells Triggers Anti-Inflammatory Macrophage Reprogramming. PLOS ONE (2012).
3. Pre-Treatment of Recombinant Mouse MFG-E8 Downregulates LPS-Induced TNF-α Production in Macrophages via STAT3-Mediated SOCS3 Activation. PLOS ONE (2011).
4. Milk Fat Globule-EGF Factor VIII in Sepsis and Ischemia-Reperfusion Injury. Molecular Medicine (2010).
5. Milk Fat Globule-Epidermal Growth Factor 8 Is Decreased in Intestinal Epithelium of Ulcerative Colitis Patients and Thereby Causes Increased Apoptosis and Impaired Wound Healing. Molecular Medicine (2011).
6. MFG-E8, a clearance glycoprotein of apoptotic cells, as a new marker of disease severity in chronic obstructive pulmonary disease. Brazilian Journal of Medical and Biological Research (2015).