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More Genes relevant to Phagocytosis - Apoptosis and the role of Retinoids

In previous posts we presented results that originated from Machine Learning and Network Analysis. These results can be used as hypotheses as to what can be the potential causes behind the Devastating syndromes that are discussed in the first post.

It should be stressed that according to the hypotheses being generated by these methods it appears that there is a combination of factors at play. So far we presented many of these factors such as Bile Acid Homeostasis, Apoptosis of Cells, Endoplasmic Reticulum Stress, The Unfolded Protein Response, Myosins, etc). 

Please see below the following figure which is taken from a paper called "Impaired clearance of apoptotic cells in chronic inflammatory diseases: Therapeutic implications" : [1]

We now look at the same Figure but we annotate with a blue rectangle the Topics presented in this Blog that were selected with Machine Learning and / or Network Analysis. In red rectangles we have topics that were not selected by these methods as most of them have not been part of the input data (apart from Retinoids and RXR Receptor) :

 We immediately see well known Topics as these were presented in this Blog : PPARs, LXR, MERTK, Phagosomes, Macrophages, Actin, Phagocytosis, Oxysterols, Protein S (PROS1), GAS6 .

We now look at some of the topics that are being annotated with a Red rectangle :


According to [2] :

"This gene encodes a member of the dedicator of cytokinesis protein family. Dedicator of cytokinesis proteins act as guanine nucleotide exchange factors for small Rho family G proteins. The encoded protein regulates the small GTPase Rac, thereby influencing several biological processes, including phagocytosis and cell migration. Overexpression of this gene has also been associated with certain cancers."


 According to [3] :

"The protein encoded by this gene interacts with the dedicator of cytokinesis 1 protein to promote phagocytosis and effect cell shape changes"

and more importantly, let's look at what happens if a combination of mutations on both sites occurs :

"Mutation of both interaction sites for DOCK180 on ELMO1 will lead to the disruption of the ELMO1-DOCK180 complex. ELMO1 complexed with both DOCK180 and CrkII leads to maximal efficiency of phagocytosis in the cell. This complex of molecules happens upstream of Rac during phagocytosis"

 -STAB2 (Stabilin-2)

In [4] we find that Stabilin 2 is highly expressed in sinusoidal endothelial cells of liver, spleen and lymph nodes and interacts with GULP1 (also shown in the figure).

In [2] we read :

"Phagocytic receptors activate two evolutionary conserved pathways both converging on the activation of Rac-1, a small GTPase (45) (Figure 1). The first pathway is initiated by MerTk or integrin av/b5 receptors (46, 47), resulting in association of the adaptor protein ELMO with the Rac GEF DOCK180 forming a bipartite GEF (48). Recruitment of the ELMO/DOCK180 complex to the cell membrane might require the adaptor protein CrkII, but binding of ELMO to the carboxyl terminus of BAI1 also recruits DOCK180 to the phagocytic membranes (33). The second pathway activating the Rac is initiated by LRP1 (CD91) (49) or by stabilin-2 receptors followed by recruitment of the adaptor protein GULP"

 Therefore we see  that we  two different pathways exist that they ultimately activate Rac-1 (RAC1) :

The first pathway involves : MERTK, ELMO1/DOCK180 and the second pathway uses CD91 or STAB2 and subsequently GULP


From [5] we read :

"LRP1 is a member of the LDLR family and ubiquitously expressed in multiple tissues, though it is most abundant in vascular smooth muscle cells (SMCs), hepatocytes, and neurons.[8][9] LRP1 plays a key role in intracellular signaling and endocytosis, which thus implicate it in many cellular and biological processes, including lipid and lipoprotein metabolism, protease degradation, platelet derived growth factor receptor regulation, integrin maturation and recycling, regulation of vascular tone, regulation of blood brain barrier permeability, cell growth, cell migration, inflammation, and apoptosis, as well as diseases such as neurodegenerative diseases, atherosclerosis, and cancer"


 According to [1] :

"Following engulfment, apoptotic cell derived lipids (oxysterols and fatty acids) trigger the lipid-sensing LXR and PPAR receptors leading to enhanced retinoid production. Retinoid receptors together with LXR and PPARs upregulate a number of phagocytic receptors to further enhance the engulfing capacity of macrophages under conditions when the rate of apoptosis is increased."

As previously discussed, Retinoids and RXR have not been selected by any Algorithm or Network Analysis. However, it appears that they may be playing an important role to the Syndromes mentioned here particularly since they interact with LXR and  PPARs.


In  [6] we read the following  :

"The clearance of apoptotic cells is critical for the control of tissue homeostasis; however, the full range of receptors on phagocytes responsible for the recognition of apoptotic cells remains to be identified. Here we found that dendritic cells (DCs), macrophages and endothelial cells used the scavenger receptor SCARF1 to recognize and engulf apoptotic cells via the complement component C1q. Loss of SCARF1 impaired the uptake of apoptotic cells"
and :
"Consequently, in SCARF1-deficient mice, dying cells accumulated in tissues, which led to a lupus-like disease, with the spontaneous generation of autoantibodies to DNA-containing antigens, activation of cells of the immune system, dermatitis and nephritis. The discovery of such interactions of SCARF1 with C1q and apoptotic cells provides insight into the molecular mechanisms involved in the maintenance of tolerance and prevention of autoimmune disease."

We therefore further hypothesise that  Genes being mentioned here could also be important to the syndromes discussed but also -given specific combinations of mutations- to several other diseases as well.



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