**4. Receptor synergy during phagocytosis**

The engagement of apoptotic cells for example is achieved by action of CD36 that binds oxidized PS, and integrins that bind PS-bridging proteins, including MFG-E8. Signaling by integrins to the main actin cytoskeleton at sites of apoptotic corpse engagement involves Rac activation and completion of internalization which requires myosin [13]. The avidity of an interaction is normally thought of as the proportion pf the number of copies of a single receptor type engaged at a time. Therefor in the context of phagocytosis myriad different receptors exist and physiological targets expose a variety of ligands. This phenomenon raises the chances of combined avidity,

#### **Figure 1.**

*The figure show the main steps of phagocytosis in dead cells and microbes.*

conferred by simultaneous engagement of multiple unrelated receptor types. Thus a microbe exposed in serum is likely to be recognized immediately by pattern recognition receptors like Dectin (**Figure 1**) [15].

#### **4.1 The Phagocytosis Process**

These are the main steps that facilitate phagocytosis of microbes and dead cells. To what extent does the phagocyte decode the microbial genetics to be able to mount an appropriate response? There is a clue on the fact that there are cations like magnesium and calcium. These cations must be present in in the extracellular fluid in sufficient quantities for macrophages to ingest a variety of microbes with ease, however C3 opsonized particles are more easily ingested with a much lower divalent amounts of cations than unopsonised ones. Therefore C3 seem to have increase ingestion by potentiating the effect of cations [16].

### **5. The schematic shows the process of phagocytosis**

IMAGE FROM Molecular and Cellular Immunology by Saunders 4th edition. page35. Pathogens could be ingested by different membrane receptors on the phagocytes. Some receptors bind microbes directly while others will only bind opsonized pathogens. But remember that the Mac-1 integrins binds microbes opsonized with complement protein e.g. C3. The pathogens are internalized in the phagosome which then fuse with lysosomes to form phagolysosomes. Where the microbes are killed by ROS and nitrogen intermediate enzymes. (NO, nitric oxide, ROS, reactive oxygen species).

#### **5.1 Step one: recognition of the microbe**

Neutrophils and other macrophages are always exposed to cells that they ignore but instead will specifically take on different microbes and particles. The specificity is due to the presence of different of receptors on these cells that recognize microbes [17]. Despite the various differences all phagocytic targets have a common characteristic that is they present the phagocyte multivalent arrays of ligands, a critical feature for the activation of most phagocytic receptors that are invariably activated by clustering laterally in the plane of the membrane therefore unlike GPCRs or growth factor receptors that undergo trans membrane remodulation upon binding with their ligands, phagocytic receptors are stimulated when their fluid cation quantities are elevated as they get immobilized by closely apposed stationary ligands [17]. Pathogen ligands for most phagocytic receptor include various protein receptor and complex lipids such as lipopolysaccharides, teichoic acids and mycobacterial lipids [18]. The none opsonic receptors that are expressed by professional phagocytes include lectin like recognition molecules such as CD169, CD33 and the related receptors specifically for sialylated membrane residues [19]. You recall that some receptors may bind these pathogen associated molecules) PAMPs (and still fail to initiate phagocytosis majorly due to poor preparation or priming. TLRs and some G-protein coupled receptors prime the cell for phagocytosis by inducing inverted activation of phagocytic integrins [20]. Phagocytes also express some other types of receptors like the Dectin-1 which for fungal betaglucan [21] with well-defined signaling capacity, other related lectin include MICL, Dectin 2,Mincle and DNGR-1 with other group of scavenger receptors like SR-A, MARCO and CD36 that have different domain structures which work by overlapping of recognition apoptotic [22].

#### **5.2 Step two: particle internalization**

When a particle binds with a phagocyte receptor, various signaling pathway events are triggered to activate phagocytosis. Most changes in membrane conformation and the actin cytoskeleton take place which leads to the formation of pseudopods that the engulf the microbe [23]. The Fcy receptors get activated in the plane of the phagocyte membrane when they aggregate after binding to their IgG ligands which then cover the particle to be ingested [24].

### **5.3 Step three: phagocyte formation**

Signaling events are triggered to start phagocytosis immediately when the phagocyte receptors engage the microorganism. This is followed by membrane remodeling and the cytoskeleton leading to the formation of pseudopods that engulf the microbes. This causes lipids to associate and dissociate from the membrane of phagosome in orderly way [25]. A depression of the membrane (a phagocytic up) is made at the point of contact of the phagosome with the microbe, then the membrane protrusions fuse at the distal end to finally seal off the new phagosome [26, 27]. When the Fcy Receptors aggregate after binding to their IgG ligands that cover the particle to be ingested. Clustering of activating receptors FcyRs results in phosphorylation of the immunoreceptor tyrosine based activation motifs (ITAMs) present in the cytoplasmic domain of the receptors in the case of FcyRIIa and FcyRIIc or in an FcR common Y-chain [24, 28].

A number of receptors are attached on the phagocyte that cooperate to facilitate phagocytosis and ingestion. The interactions of receptors are improved with possible targets by (i) creating active protrusions that allow the cell to explore larger area increasing the chances for receptors to engage their ligands. (ii) selectively removing of the larger glycoproteins allowing the receptors to diffuse more freely on the membrane [29]. The phosphatase CD45 can extend more than 40 nm from the cell membrane [30] and it's a real obstacle for most phagocytic receptors, therefore removing these large molecules could drastically improve receptor binfding.CD45 was first identified during the Dectin 1 mediated phagocytosis in a phagocytic synapse [31] for its resemblance with the T lymphocyte immune synapse. When the T cell receptor TCR molecules on the T lymphocyte interact with the MHC molecules on an antigen presenting cell APC, a central cluster of engaged TCRs are surrounded by a ring of integrin LFA-1 molecules and CD45 is excluded from the center [32].
