-
International Journal of Molecular... May 2022Sjögren's syndrome (SS) is a chronic autoimmune disease that affects exocrine glands, primarily the salivary and lachrymal glands. It is characterized by... (Review)
Review
Sjögren's syndrome (SS) is a chronic autoimmune disease that affects exocrine glands, primarily the salivary and lachrymal glands. It is characterized by lymphoplasmacytic infiltration of the glandular tissues, ultimately leading to their dysfunction and destruction. Besides classic dry eyes and dry mouth defined as sicca syndrome, patients affected by the disease also typically display symptoms such as fatigue, pain and in more than 50% of cases, systemic manifestations such as arthritis, interstitial lung involvement, neurological involvement and an increased risk of lymphoma. The pathophysiological mechanisms underlying SS still remain elusive. The crucial role of innate immunity has been advocated in recent years regarding the pathogenesis of pSS, especially in the initiation and progression toward autoimmunity. Alarmins are endogenous molecules that belong to the large family of damage associated molecular pattern (DAMP). Alarmins are rapidly released, ensuing cell injury and interacting with pattern recognition receptors (PRR) such as toll-like receptors (TLR) to recruit and activate cells of the innate immune system and to promote adaptive immunity responses. This review highlights the current knowledge of various alarmins and their role in the pathogenesis of pSS.
Topics: Alarmins; Humans; Lacrimal Apparatus; Sjogren's Syndrome; Toll-Like Receptors; Xerostomia
PubMed: 35628481
DOI: 10.3390/ijms23105671 -
Journal of the American Society of... Sep 2016Kidney injury implies danger signaling and a response by the immune system. The inflammasome is a central danger recognition platform that triggers local and systemic... (Review)
Review
Kidney injury implies danger signaling and a response by the immune system. The inflammasome is a central danger recognition platform that triggers local and systemic inflammation. In immune cells, inflammasome activation causes the release of mature IL-1β and of the alarmin IL-1α Dying cells release IL-1α also, independently of the inflammasome. Both IL-1α and IL-1β ligate the same IL-1 receptor (IL-1R) that is present on nearly all cells inside and outside the kidney, further amplifying cytokine and chemokine release. Thus, the inflammasome-IL-1α/IL-β-IL-1R system is a central element of kidney inflammation and the systemic consequences. Seminal discoveries of recent years have expanded this central paradigm of inflammation. This review gives an overview of arising concepts of inflammasome and IL-1α/β regulation in renal cells and in experimental kidney disease models. There is a pipeline of compounds that can interfere with the inflammasome-IL-1α/IL-β-IL-1R system, ranging from recently described small molecule inhibitors of NLRP3, a component of the inflammasome complex, to regulatory agency-approved IL-1-neutralizing biologic drugs. Based on strong theoretic and experimental rationale, the potential therapeutic benefits of using such compounds to block the inflammasome-IL-1α/IL-β-IL-1R system in kidney disease should be further explored.
Topics: Alarmins; Animals; Disease Models, Animal; Humans; Inflammasomes; Interleukin-1alpha; Interleukin-1beta; Kidney Diseases
PubMed: 27516236
DOI: 10.1681/ASN.2016020177 -
Current Opinion in Genetics &... Oct 2016Wounding of tissue barriers, such as epithelia, disrupts homeostasis and allows infection. Within minutes, animals detect injury and respond to it by recruitment of... (Review)
Review
Wounding of tissue barriers, such as epithelia, disrupts homeostasis and allows infection. Within minutes, animals detect injury and respond to it by recruitment of phagocytes and barrier breach closure. The signals that activate these first events are scarcely known. Commonly considered are cytoplasmic factors released into the extracellular space by lysing cells (Damage Associated Molecular Patterns, DAMPs). DAMPs activate inflammatory gene transcription through pattern recognition receptors. But the promptness of wound responses is difficult to explain by transcriptional mechanisms alone. This review highlights the emerging role of nonlytic stress signals in the rapid detection of wounds.
Topics: Alarmins; Animals; Drosophila; Extracellular Space; Homeostasis; Humans; Phagocytes; Receptors, Pattern Recognition; Wound Healing; Wounds and Injuries; Zebrafish
PubMed: 27266971
DOI: 10.1016/j.gde.2016.05.001 -
Frontiers in Cellular and Infection... 2022Sepsis, a life-threatening organ dysfunction, is not caused by direct damage of pathogens and their toxins but by the host's severe immune and metabolic dysfunction... (Review)
Review
Sepsis, a life-threatening organ dysfunction, is not caused by direct damage of pathogens and their toxins but by the host's severe immune and metabolic dysfunction caused by the damage when the host confronts infection. Previous views focused on the damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), including metabolic proinflammatory factors in sepsis. Recently, new concepts have been proposed to group free fatty acids (FFAs), glucose, advanced glycation end products (AGEs), cholesterol, mitochondrial DNA (mtDNA), oxidized phospholipids (OxPLs), ceramides, and uric acid into metabolism-associated molecular patterns (MAMPs). The concept of MAMPs will bring new guidance to the research and potential treatments of sepsis. Nowadays, sepsis is regarded as closely related to metabolic disorders, and MAMPs play an important role in the pathogenesis and development of sepsis. According to this view, we have explained MAMPs and their possible roles in the pathogenesis of sepsis. Next, we have further explained the specific functions of different types of MAMPs in the metabolic process and their interactional relationship with sepsis. Finally, the therapeutic prospects of MAMPs in sepsis have been summarized.
Topics: Alarmins; Humans; Mitochondria; Pathogen-Associated Molecular Pattern Molecules; Sepsis
PubMed: 35719361
DOI: 10.3389/fcimb.2022.915099 -
American Journal of Physiology. Cell... May 2020Danger sensing is one of the most fundamental evolutionary features enabling multicellular organisms to perceive potential threats, escape from risky situations, fight...
Danger sensing is one of the most fundamental evolutionary features enabling multicellular organisms to perceive potential threats, escape from risky situations, fight actual intruders, and repair damage. Several endogenous molecules are used to "signal damage," currently referred to as "alarmins" or "damage-associated molecular patterns" (DAMPs), most being already present within all cells (preformed DAMPs), and thus ready to be released, and others neosynthesized following injury. Over recent years it has become overwhelmingly clear that adenosine 5'-triphosphate (ATP) is a ubiquitous and extremely efficient DAMP (thus promoting inflammation), and its main metabolite, adenosine, is a strong immunosuppressant (thus dampening inflammation). Extracellular ATP ligates and activates the P2 purinergic receptors (P2Rs) and is then degraded by soluble and plasma membrane ecto-nucleotidases to generate adenosine acting at P1 purinergic receptors (P1Rs). Extracellular ATP, P2Rs, ecto-nucleotidases, adenosine, and P1Rs are basic elements of the purinergic signaling network and fundamental pillars of inflammation.
Topics: Adenosine; Adenosine Triphosphatases; Adenosine Triphosphate; Alarmins; Animals; Cell Membrane; Humans; Immunosuppressive Agents; Inflammation; Receptors, Purinergic P1; Receptors, Purinergic P2; Signal Transduction
PubMed: 32159362
DOI: 10.1152/ajpcell.00053.2020 -
Nature Immunology Feb 2021Inflammatory caspase sensing of cytosolic lipopolysaccharide (LPS) triggers pyroptosis and the concurrent release of damage-associated molecular patterns (DAMPs)....
Inflammatory caspase sensing of cytosolic lipopolysaccharide (LPS) triggers pyroptosis and the concurrent release of damage-associated molecular patterns (DAMPs). Collectively, DAMPs are key determinants that shape the aftermath of inflammatory cell death. However, the identity and function of the individual DAMPs released are poorly defined. Our proteomics study revealed that cytosolic LPS sensing triggered the release of galectin-1, a β-galactoside-binding lectin. Galectin-1 release is a common feature of inflammatory cell death, including necroptosis. In vivo studies using galectin-1-deficient mice, recombinant galectin-1 and galectin-1-neutralizing antibody showed that galectin-1 promotes inflammation and plays a detrimental role in LPS-induced lethality. Mechanistically, galectin-1 inhibition of CD45 (Ptprc) underlies its unfavorable role in endotoxin shock. Finally, we found increased galectin-1 in sera from human patients with sepsis. Overall, we uncovered galectin-1 as a bona fide DAMP released as a consequence of cytosolic LPS sensing, identifying a new outcome of inflammatory cell death.
Topics: Adult; Aged; Aged, 80 and over; Alarmins; Animals; Case-Control Studies; Disease Models, Animal; Endotoxemia; Female; Galectin 1; HeLa Cells; Humans; Inflammation; Inflammation Mediators; Intracellular Signaling Peptides and Proteins; Leukocyte Common Antigens; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Necroptosis; Phosphate-Binding Proteins; RAW 264.7 Cells; Sepsis; Signal Transduction; Up-Regulation
PubMed: 33398185
DOI: 10.1038/s41590-020-00844-7 -
Oncotarget Sep 2015
Topics: Alarmins; Animals; Atherosclerosis; Cell Death; Gene Deletion; HMGB1 Protein; Homeostasis; Humans; Inflammation; Liver; Mice; Neoplasms; Reperfusion Injury; Signal Transduction
PubMed: 26309086
DOI: 10.18632/oncotarget.5243 -
Allergology International : Official... Oct 2021Unlike other barrier epithelia of internal organs, the stratified squamous epithelium of the skin is always exposed to the external environment. However, the robust... (Review)
Review
Unlike other barrier epithelia of internal organs, the stratified squamous epithelium of the skin is always exposed to the external environment. However, the robust barrier structure and function of the skin are highly resistant against external insults so as to not easily allow foreign invasions. Upon sensing danger signals, the innate immunity system is promptly activated. This process is mediated by alarmins, which are released passively from damaged cells. Nuclear alarmins or stressorins are actively released from intact cells in response to various cellular stresses. Alarmins/stressorins are deeply involved in the disease processes of chronic skin disorders of an unknown cause, such as rosacea, psoriasis, and atopic dermatitis. Furthermore, alarmins/stressorins are also induced in the congenital skin disorders of ichthyosis and keratoderma due to defective keratinization. Studies on alarmin activation and its downstream pathways may help develop novel therapeutic agents for intractable skin disorders.
Topics: Alarmins; Animals; Humans; Skin Diseases
PubMed: 34127380
DOI: 10.1016/j.alit.2021.05.005 -
Cells Jun 2023Nuclear protein prothymosin α (ProTα) is a unique member of damage-associated molecular patterns (DAMPs)/alarmins. ProTα prevents neuronal necrosis by causing a cell... (Review)
Review
Nuclear protein prothymosin α (ProTα) is a unique member of damage-associated molecular patterns (DAMPs)/alarmins. ProTα prevents neuronal necrosis by causing a cell death mode switch in serum-starving or ischemic/reperfusion models in vitro and in vivo. Underlying receptor mechanisms include Toll-like receptor 4 (TLR4) and G-coupled receptor. Recent studies have revealed that the mode of the fatal stress-induced extracellular release of nuclear ProTα from cortical neurons in primary cultures, astrocytes and C6 glioma cells has two steps: ATP loss-induced nuclear release and the Ca-mediated formation of a multiple protein complex and its extracellular release. Under the serum-starving condition, ProTα is diffused from the nucleus throughout the cell due to the ATP loss-induced impairment of importin α-mediated nuclear transport. Subsequent mechanisms are all Ca-dependent. They include the formation of a protein complex with ProTα, S100A13, p40 Syt-1 and Annexin A2 (ANXA2); the fusion of the protein complex to the plasma membrane via p40 Syt-1-Stx-1 interaction; and TMEM16F scramblase-mediated ANXA2 flop-out. Subsequently, the protein complex is extracellularly released, leaving ANXA2 on the outer cell surface. The ANXA2 is then flipped in by a force of ATP8A2 activity, and the non-vesicular release of protein complex is repeated. Thus, the ANXA2 flop-out could play key roles in a new type of non-vesicular and non-classical release for DAMPs/alarmins, which is distinct from the modes conducted via gasdermin D or mixed-lineage kinase domain-like pseudokinase pores.
Topics: Humans; Alarmins; Annexin A2; Necrosis; Nuclear Proteins; Adenosine Triphosphate
PubMed: 37371039
DOI: 10.3390/cells12121569 -
International Journal of Molecular... Jan 2021Chronic inflammation contributes to the development and progression of various tumors. Especially where the inflammation is mediated by cells of the innate immune... (Review)
Review
Chronic inflammation contributes to the development and progression of various tumors. Especially where the inflammation is mediated by cells of the innate immune system, the NLRP3 inflammasome plays an important role, as it senses and responds to a variety of exogenous and endogenous pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The NLRP3 inflammasome is responsible for the maturation and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 and for the induction of a type of inflammatory cell death known as pyroptosis. Overactivation of the NLRP3 inflammasome can be a driver of various diseases. Since leukemia is known to be an inflammation-driven cancer and IL-1β is produced in elevated levels by leukemic cells, research on NLRP3 in the context of leukemia has increased in recent years. In this review, we summarize the current knowledge on leukemia-promoting inflammation and, in particular, the role of the NLRP3 inflammasome in different types of leukemia. Furthermore, we examine a connection between NLRP3, autophagy and leukemia.
Topics: Alarmins; Animals; Autophagy; Carcinogenesis; Disease Progression; Gene Expression Regulation, Leukemic; Humans; Immunity, Innate; Inflammasomes; Inflammation; Interleukin-18; Interleukin-1beta; Leukemia; NLR Family, Pyrin Domain-Containing 3 Protein; Pathogen-Associated Molecular Pattern Molecules; Pyroptosis; Signal Transduction
PubMed: 33525345
DOI: 10.3390/ijms22031271