Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation

Abstract

Cell death and injury often lead to release or exposure of intracellular molecules called damage-associated molecular patterns (DAMPs) or cell death-associated molecules. These molecules are recognized by the innate immune system by pattern recognition receptors - the same receptors that detect pathogen-associated molecular patterns, thus revealing similarities between pathogen-induced and non-infectious inflammatory responses. Many DAMPs are derived from the plasma membrane, nucleus, endoplasmic reticulum and cytosol. Recently, mitochondria have emerged as other organelles that function as a source of DAMPs. Here, we highlight the significance of mitochondrial DAMPs and discuss their contribution to inflammation and development of human pathologies.

Consensus guidelines for the detection of immunogenic cell death

“…41,46,115,116,[144][145][146][147] In addition, many DAMPs have been shown to contribute to the immunogenicity of cell death in a limited amount of experimental scenarios. These include immunostimulatory cytokines like interferon a (IFNa), various chaperones of the heat-shock protein (HSP) family, notably heat shock 70kDa protein 1A (HSPA1A, best known as HSP70) and heat shock protein 90kDa a (cytosolic), class A member 1 (HSP90AA1, best known as HSP90), 65,71,85,90,145,[150][151][152][153] sphingomyelin metabolites (e.g., ceramide and sphingosine-1-phosphate), 154 a plethora of mitochondrial products (e.g., mitochondrial DNA, N-formylated peptides, cardiolipin), [155][156][157] cytosolic components like urate and F-actin, [158][159][160][161] as well as products of the breakdown of the extracellular matrix (e.g., hyaluronan fragments). 162,163 CALR gets exposed on the cell surface early in the course of ICD, i.e., before the apoptosis-associated shuffling of phosphatidylserine between the inner and outer leaflet of the plasma membrane.…”

Cellular and molecular mechanisms in liver fibrogenesis

“…Several DAMPs can be released or generated into the extracellular environment by dying cells or in relation to abnormal metabolism, and then trigger sterile inflammation, including proteins like: i) high-mobility group box 1 (HMGB1) [102], ii) heat shock proteins (HSPs) [103], iii) proteins of extracellular matrix generated following tissue injury (i.e., hyaluronan, heparin sulfate and biglycan) as modified/cleaved by enzymes released from dying cells or by other proteases [104,105]. Non-protein DAMPs such as ATP and uric acid (that) can be released or generated during cell injury and death [106]; mitochondria are a rich source of DAMPs like, in addition to ATP, mitochondrial DNA, formyl peptides and cytochrome C [107] which are effective stimulators of inflammation. Along these lines, inflammasomes represent a group of protein complexes able to recognize PAMPs and DAMPs and that control activation of the proteolytic enzyme caspase-1, which in turn regulates maturation of the pro-inflammatory cytokines IL-1β and IL-18 [108,109].…”

Trauma alarmins as activators of damage-induced inflammation

“…Identification of trauma alarmins and the molecular pathways that generate the immune response may provide an opportunity for the development of therapeutic agents able to modulate the response and improve outcomes. Binding of multiple ligands, dual roles for receptors, and genetic polymorphisms for cytokine production make devising immune therapeutics for trauma extremely challenging 26,51,95,96 . Nonetheless, evidence from preclinical studies supports the idea that molecular blockade reduces adverse clinical sequelae and therapeutic agents are under development 37 .…”

“…Reactive oxygen species are generated by mitochondria during apoptosis and released in conditions of cellular stress. They are known to have inflammatory capacity, but along with several other mitochondrial components their role as a trauma alarmin has not yet been examined (see review 51 ). Finally, the cell surface saccharides, heparan sulphate and hyluronan, have inflammatory capabilities through TLR4 24,83 and can instigate a SIRS response in rodents 83 .…”