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Milk Fat Globule-EGF Factor 8 and MFGM

Moving forward to Medical Topics most likely related to ME/CFS and all syndromes discussed in the first post of this blog, it is now time to focus on Milk-Fat Globule Membrane (MFGM), Gene name MFGE8.

According to Wikipedia [1] :

Milk fat globule membrane (MFGM) is a complex and unique structure composed primarily of lipids and proteins that surrounds milk fat globule secreted from the milk producing cells of humans and other mammals. It is a source of multiple bioactive compounds, including phospholipids, glycolipids, glycoproteins, and carbohydrates that have important functional roles within the brain and gut.

Machine Learning suggests a very high importance of Milk-Fat Globule Membrane and MFGE8. I believe there are a number of reasons for this. It appears that MFGE8  has several positive qualities that are beneficial for Phagocytosis and apoptotic cell clearance, Inflammation, Autoimmunity and Intestinal Barrier Integrity to name a few. Here are some excerpts from [2,3] :

Intestinal Epithelium Integrity :

The intestinal epithelium is a continuous single layer of cells that lines the intestinal tract. It provides a physical barrier that separates internal body compartments and the harmful environment of the gut lumen. Defects in epithelial barrier and immune functions can lead to infections with opportunistic and pathogenic microbes and contribute to the pathogenesis of inflammatory bowel disease (IBD). Recent studies have shown that macrophages in the underlying intestinal tissue produce milk fat globule-EGF factor 8 (MFG-E8) which directly targets intestinal epithelial cells and regulates the integrity of intestinal epithelial barrier function. 

Inflammatory Disease :

Some studies have demonstrated that MFG-E8 plays a role in inflammatory degenerative bone diseases such as RA and osteoarthritis (OA). The expression of MFG-E8 is downregulated in inflammatory conditions and has also been found to be downregulated in the sera of RA patients, while an in vitro study revealed that MFG-E8 suppresses inflammatory responses by suppressing the production of proinflammatory cytokines. Moreover, the expression of MFG-E8 is decreased in arthritic mice, and the loss of MFG-E8 exacerbated arthritis and led to more severe bone loss in mice by inducing the production of proinflammatory cytokines and the infiltration of pathogenic neutrophils in the inflamed joints

Sepsis:


Sepsis is a high lethal systemic inflammatory disease characterized by the increase in proinflammatory cytokines and the accumulation of apoptotic cells. It has been reported that MFG-E8 is correlated with sepsis. During sepsis, a large number of immune cells undergo apoptosis due to the impairment of apoptotic cell clearance, which then induces secondary necrotic cell development that dysregulates proper immune function and induces the production of proinflammatory cytokines. Therefore, studying the function of MFG-E8 could lead to promising therapeutic approaches that facilitate the clearance of apoptotic cells by MFG-E8 in sepsis.

and also from [5]

Milk fat globule-EGF factor VIII (MFG-E8), which is mainly produced by macrophages and dendritic cells, is an opsonin for apoptotic cells and acts as a bridging protein between apoptotic cells and phagocytes. Recently, we have shown that MFG-E8 expression is decreased in experimental sepsis and I/R injury models. Exogenous administration of MFG-E8 attenuated the inflammatory response as well as tissue injury and mortality through the promotion of phagocytosis of apoptotic cells. In this review, we describe novel information available about the involvement of MFG-E8 in the pathophysiology of sepsis and I/R injury, and the therapeutic potential of exogenous MFG-E8 treatment for those conditions.

Phagocytosis and Apoptotic Cell Clearance:

The most remarkable function of MFG-E8 is the phagocytosis and removal of apoptotic cells. The recognition of apoptotic cells is thought to be accomplished by the release of so-called “eat-me” signals from apoptotic cells, which recruit phagocytes such as macrophages and dendritic cells, leading to the clearance of dying cells 


It is now time to re-visit the previous post where the following figure taken from [4] was shown :



There are some interesting points that need to be highlighted regarding the figure shown above :

1) The relevance of MFGE8 (located under the red rectangle) with Inflammation and Autoimmunity (located on the bottom side of the figure)

2) The mention of several topics discussed previously in this blog. More specifically LXR, PPAR, Fatty Acids, Oxysterols, Vitamin K related Genes such as Gas6 and ProS, Reverse Cholesterol Transport, Cholesterol Efflux. 


In the next post we will put together all posts discussed so far and form a Hypothesis as to what may be happening with individuals having any of the Syndromes discussed in this Blog.


References 






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