Damage-associated molecular pattern

Damage-associated molecular patterns (DAMPs), also known as danger-associated molecular patterns, are molecules released by stressed cells undergoing necrosis that act as endogenous danger signals to promote and exacerbate the inflammatory response. DAMPs are a component of the innate immune system, initiating and perpetuating the immune response in the presence of injury or disease without the need for antibodies. This contrasts with pathogen-associated molecular patterns (PAMPs), which are molecules associated with groups of pathogens and are recognized by pattern recognition receptors (PRRs) of the innate immune system.

Overview

DAMPs can originate from various cellular components, including the nucleus, mitochondria, or cytoplasm, and can be proteins, DNA, RNA, or even metabolites. When cells are damaged by physical injury, infection, ischemia, or toxin exposure, they release DAMPs. These molecules then bind to PRRs such as Toll-like receptors (TLRs) and receptor for advanced glycation endproducts (RAGE), among others, on immune cells like macrophages and dendritic cells. This binding initiates signaling pathways that lead to the production of pro-inflammatory cytokines, chemokines, and type I interferons, which are crucial for the recruitment and activation of further immune cells to the site of injury or infection.

Types of DAMPs

Several types of DAMPs have been identified, including but not limited to:

• High mobility group box 1 (HMGB1): A nuclear protein that, when released into the extracellular space, acts as a cytokine and promotes inflammation.
• ATP: Extracellular ATP can act as a DAMP through its receptor P2X purinoceptor 7 (P2X7) on immune cells, leading to the activation of the inflammasome and production of IL-1β.
• Uric acid crystals: These can activate the NLRP3 inflammasome, leading to the production of IL-1β.
• S100 proteins: A group of proteins that, when released extracellularly, can act as DAMPs to stimulate the immune response.
• Heat shock proteins: These proteins can signal through TLRs and promote an inflammatory response when released from stressed or dying cells.

Role in Disease

While DAMPs play a crucial role in the body's defense against injury and infection, their overproduction or inappropriate release can contribute to the pathogenesis of various diseases, including autoimmune diseases, cancer, and chronic inflammatory conditions. For example, in autoimmune diseases, the immune system may recognize self-DNA or other DAMPs as foreign, leading to an inappropriate immune response against the body's own cells. In cancer, the release of DAMPs can promote tumor growth and metastasis by creating a pro-inflammatory microenvironment.

Therapeutic Implications

Understanding the role of DAMPs in disease has led to the exploration of therapeutic strategies aimed at modulating their activity. For instance, inhibitors of PRRs or signaling pathways activated by DAMPs are being investigated as potential treatments for inflammatory diseases and cancer. Additionally, therapies that target the clearance of DAMPs or prevent their release from dying cells are also under consideration.

See Also

• Innate immune system
• Inflammation
• Autoimmune disease
• Cancer
• Necrosis
• Pathogen-associated molecular pattern