Page last updated: 2024-10-24

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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Proteins (1)

ProteinDefinitionTaxonomy
Protein-glutamine gamma-glutamyltransferase 2A protein-glutamine gamma-glutamyltransferase 2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P21980]Homo sapiens (human)

Compounds (16)

CompoundDefinitionClassesRoles
1-(2-naphthalenyl)-3-[(phenylmethyl)-propan-2-ylamino]-1-propanoneZM39923: structure in first sourcenaphthalenes
beta-lapachonebeta-lapachone : A benzochromenone that is 3,4-dihydro-2H-benzo[h]chromene-5,6-dione substituted by geminal methyl groups at position 2. Isolated from Tabebuia avellanedae, it exhibits antineoplastic and anti-inflammatory activities.

beta-lapachone: antineoplastic inhibitor of reverse transcriptase, DNA topoisomerase, and DNA polymerase
benzochromenone;
orthoquinones
anti-inflammatory agent;
antineoplastic agent;
plant metabolite
vitamin k 3Vitamin K 3: A synthetic naphthoquinone without the isoprenoid side chain and biological activity, but can be converted to active vitamin K2, menaquinone, after alkylation in vivo.1,4-naphthoquinones;
vitamin K
angiogenesis inhibitor;
antineoplastic agent;
EC 3.4.22.69 (SARS coronavirus main proteinase) inhibitor;
human urinary metabolite;
nutraceutical
5-bromoisatinindolesanticoronaviral agent
isatintribulin: endogenous MONOAMINE OXIDASE inhibitory activity extractable into ethyl acetate found in brain and many mammalian tissues and fluids; ISATIN is a major component; produced in excess following alcohol withdrawal;indoledioneEC 1.4.3.4 (monoamine oxidase) inhibitor;
plant metabolite
indirubin
5-Chloro-1H-indole-2,3-dioneindolesanticoronaviral agent
5-iodoisatin5-iodoisatin: structure in first sourceindolesanticoronaviral agent
isoindigotinisoindigotin: used in treatment of chronic granulocytic leukemia; structure given in first source
n-phenylacrylamideN-phenylacrylamide: structure in first source
nsc 953971,4-naphthoquinones
ag-213tyrphostin 47: inhibits protein-tyrosine kinase activity of EGF-R both in vitro and in living cells;
rottlerinrottlerin : A chromenol that is 2,2-dimethyl-2H-chromene substituted by hydroxy groups at positions 5 and 7, a 3-acetyl-2,4,6-trihydroxy-5-methylbenzyl group at position 6 and a (1E)-3-oxo-1-phenylprop-1-en-3-yl group at position 8. A potassium channel opener, it is isolated from Mallotus philippensis.

rottlerin: an angiogenesis inhibitor; an inhibitor of protein kinase Cdelta (PKCdelta) and calmodulin kinase III; RN refers to (E)-isomer; do not confuse this chalcone with an anthraquinone that is also called rottlerin (RN 481-72-1);
aromatic ketone;
benzenetriol;
chromenol;
enone;
methyl ketone
anti-allergic agent;
antihypertensive agent;
antineoplastic agent;
apoptosis inducer;
K-ATP channel agonist;
metabolite
gw-5074
glutaminase
guanylyl imidodiphosphateguanosine 5'-[beta,gamma-imido]triphosphate : A nucleoside triphosphate analogue that is GTP in which the oxygen atom bridging the beta- to the gamma- phosphate is replaced by a nitrogen atom A non-hydrolyzable analog of GTP, it binds tightly to G-protein in the presence of Mg(2+).

Guanylyl Imidodiphosphate: A non-hydrolyzable analog of GTP, in which the oxygen atom bridging the beta to the gamma phosphate is replaced by a nitrogen atom. It binds tightly to G-protein in the presence of Mg2+. The nucleotide is a potent stimulator of ADENYLYL CYCLASES.
nucleoside triphosphate analogue