What is necrosis ?

Necrosis is a form of cell death characterized by the uncontrolled breakdown of cellular components, resulting in inflammation and tissue damage. Understanding necrotic pathway is essential for elucidating its role in various diseases, including ischemic injuries, infections, and chronic inflammatory conditions. This pathway involves specific biomarkers, molecular mechanisms, and signaling pathways that orchestrate the necrotic process.

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Overview of apoptosis and necrosis pathways. Both apoptosis and necrosis can be mediated through pathways that involve death receptors or mitochondria, resulting in four distinct pathways: 1) death receptor-mediated apoptosis, 2) death receptor-mediated necrosis (necroptosis), 3) mitochondrial-mediated apoptosis, and 4) mitochondrial-mediated necrosis.

Types of necrosis

There are several recognized types of uncontrolled cell death, each with distinct characteristics and implications:

Coagulative: Commonly associated with ischemia or infarction, this type leads to the firm, pale appearance of affected tissues.
Liquefactive: Characterized by the transformation of tissue into a liquid viscous mass, often seen in brain injuries and bacterial infections.
Caseous: Typically associated with tuberculosis infections, it resembles cheese-like (caseous) necrosis.
Fat: Resulting from the destruction of adipose tissue, often due to enzymatic action or trauma.
Fibrinoid: Associated with immune-mediated vascular damage, this type shows deposition of fibrin-like protein in blood vessels.
Gangrenous: Refers to uncontrolled cell death in a significant area of tissue due to loss of blood supply, classified as dry or wet gangrene.

Mechanisms of necrosis

Uncontrolled cell death is primarily caused by environmental factors that overwhelm cellular homeostasis, including:

Ischemia: Lack of blood flow leading to oxygen deprivation.
Toxins: Exposure to harmful substances, whether endogenous or exogenous.
Infections: Pathogenic microorganisms causing direct cell damage.
Trauma: Physical injury leading to cell death

The cellular events following uncontrolled cell death typically involve mitochondrial dysfunction, ATP depletion, and the disruption of cellular membranes, culminating in cell lysis and the release of intracellular contents that can provoke an inflammatory response.

Several key biomarkers associated with uncontrolled cell death High Mobility Group Box 1 (HMGB1) and Lactate Dehydrogenase (LDH).

Signaling pathways involved in uncontrolled cell death

Several signaling pathways play crucial roles in regulating uncontrolled cell death, including:

RIPK Pathway: The RIPK pathway plays a central role in necroptosis. When apoptosis is inhibited, RIPK1 can activate RIPK3, leading to the formation of the necrosome complex that triggers necrotic cell death.
Caspase-independent Pathways: Unlike apoptosis, which involves caspase activation, uncontrolled cell death often occurs through caspase-independent mechanisms. The absence of caspase activity in certain models supports the idea that necrosis can be a primary process rather than secondary to apoptosis.
Inflammatory Signaling: Inflammasomes, particularly NLRP3, can mediate necrosis-associated inflammation, leading to a form of regulated necrosis called necroptosis. Necrotic cells release DAMPs like HMGB1 that activate immune responses through receptors such as Toll-like receptors (TLRs). This signaling contributes to inflammation and tissue repair processes following injury.

Recent insights into regulated necrosis

Recent studies have highlighted the concept of regulated necrosis, which includes specific forms such as necroptosis, pyroptosis, and ferroptosis. These processes are genetically programmed and play significant roles in host defense and inflammation:

Necroptosis: A programmed form of necrotic cell death that occurs in response to certain stimuli, involving receptor-interacting protein kinases (RIPK1 and RIPK3). It serves as a backup mechanism when apoptosis is inhibited.
Pyroptosis: This form is associated with inflammatory responses where gasdermin proteins mediate cell lysis and release pro-inflammatory cytokines.
Ferroptosis: A form of regulated necrosis driven by iron-dependent lipid peroxidation, contributing to various diseases including cancer and neurodegeneration.

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Necrosis biomarker list

You can check the biomarker list included in this pathway, see below:

Species : Homo sapiens (human)

Human signaling pathways

Signaling Pathways	Product ref	Informations
Necrosis	NE1H1	Download biomarker list

Species : Mus musculus (mouse)

Mouse signaling pathways

Signaling Pathways	Product ref	Informations
Necrosis	NE1M1	Download biomarker list

Species : Rattus norvegicus (rat)

Rat signaling pathways

Signaling Pathways	Product ref	Informations
Necrosis	*******	Biomarker list in progress.

Species : Sus Scrofa (Pig)

Pig Necrosis

Signaling Pathways	Product ref	Informations
Necrosis	*******	Biomarker list in progress.

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Bibliography

1. Park W, et al. Diversity and complexity of cell death: a historical review. Exp Mol Med. (2023);55(8):1573-1594.

2. Bencze M. Mechanisms of Myofibre Death in Muscular Dystrophies: The Emergence of the Regulated Forms of Necrosis in Myology. Int J Mol Sci. (2022)26;24(1):362.

3. Sun C, et al. Regulated necrosis in COVID-19: A double-edged sword. Front Immunol. (2022)25:13:917141.

4. D'Arcy MS. Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int. (2019);43(6):582-592.

5. Del Re DP, et al. Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease. Physiol Rev. 2019 Jul 31;99(4):1765–1817.

6. Peixoto MS, et al. Cell death pathways of particulate matter toxicity. Chemosphere. (2017);188:32-48.

7. Green DR, Llambi F. Cell Death Signaling. Cold Spring Harb Perspect Biol. (2015);7(12):a006080.

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