regulation of apoptotic cell clearance

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of apoptotic cell clearance. [GOC:obol]

Apoptotic cell clearance, also known as efferocytosis, is a fundamental biological process that plays a crucial role in maintaining tissue homeostasis and preventing inflammation. It involves the recognition, engulfment, and degradation of apoptotic cells by phagocytes, primarily macrophages. The process is tightly regulated by a complex interplay of signaling pathways and molecular mechanisms, ensuring efficient and timely removal of dying cells without triggering immune responses.

**Recognition:**
* Apoptotic cells undergo characteristic changes, including exposure of phosphatidylserine (PS) on the outer leaflet of the plasma membrane, a "eat me" signal recognized by phagocytes.
* Other "eat me" signals include calreticulin, oxidized lipids, and complement proteins.
* Phagocytes express receptors that specifically bind to these "eat me" signals, initiating engulfment.
* Key receptors include:
* **TIM-4 (T cell immunoglobulin and mucin domain protein 4):** Binds to PS and promotes efferocytosis.
* **MerTK (Mer tyrosine kinase):** Recognizes PS, oxidized lipids, and other apoptotic signals.
* **αvβ5 integrin:** Binds to vitronectin, a protein that promotes engulfment of apoptotic cells.

**Engulfment:**
* Once recognition occurs, the phagocyte extends pseudopods to engulf the apoptotic cell.
* Actin cytoskeleton remodeling is essential for phagocytic cup formation and engulfment.
* The engulfment process is guided by signaling pathways triggered by receptor-ligand interactions.

**Degradation:**
* Once engulfed, the apoptotic cell is delivered to a phagosome, a membrane-bound compartment.
* The phagosome fuses with lysosomes, acidic compartments containing hydrolytic enzymes that break down the engulfed cell.
* Degradation products are then recycled or released from the phagocyte.

**Regulation:**
* The regulation of apoptotic cell clearance is crucial for maintaining tissue homeostasis and preventing inflammation.
* Several signaling pathways and molecules play a role in regulating this process:
* **Anti-inflammatory signaling:** Efferocytosis triggers the release of anti-inflammatory mediators by phagocytes, dampening immune responses.
* **Cytokine production:** Phagocytes release cytokines, such as IL-10, that further suppress inflammation.
* **Apoptosis-associated factors:** Proteins like annexin V and thrombospondin-1 promote efferocytosis.
* **Phosphoinositide 3-kinase (PI3K) signaling:** PI3K pathway activation plays a role in regulating phagocytic engulfment.

**Consequences of impaired clearance:**
* Defective apoptotic cell clearance can lead to the accumulation of cellular debris, promoting inflammation, autoimmune responses, and tissue damage.
* Examples include systemic lupus erythematosus (SLE), where autoreactive antibodies target apoptotic cells, and atherosclerosis, where cholesterol-laden apoptotic cells contribute to plaque formation.

**Therapeutic implications:**
* Promoting efferocytosis has emerged as a promising therapeutic strategy for various diseases.
* Targeting receptors involved in apoptotic cell clearance, developing agents that enhance efferocytosis, or preventing the formation of autoreactive antibodies are potential therapeutic approaches.'
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