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Gastroenterology May 2019Acute pancreatitis is an inflammatory disorder of the exocrine pancreas associated with tissue injury and necrosis. The disease can be mild, involving only the pancreas,... (Review)
Review
Acute pancreatitis is an inflammatory disorder of the exocrine pancreas associated with tissue injury and necrosis. The disease can be mild, involving only the pancreas, and resolve spontaneously within days or severe, with systemic inflammatory response syndrome-associated extrapancreatic organ failure and even death. Importantly, there are no therapeutic agents currently in use that can alter the course of the disease. This article emphasizes emerging findings that stressors (environmental and genetic) that cause acute pancreatitis initially cause injury to organelles of the acinar cell (endoplasmic reticulum, mitochondria, and endolysosomal-autophagy system), and that disorders in the functions of the organelles lead to inappropriate intracellular activation of trypsinogen and inflammatory pathways. We also review emerging work on the role of damage-associated molecular patterns in mediating the local and systemic inflammatory response in addition to known cytokines and chemokine pathways. In the review, we provide considerations for correction of organelle functions in acute pancreatitis to create a discussion for clinical trial treatment and design options.
Topics: Acute Disease; Alarmins; Animals; Cytokines; Humans; Inflammation Mediators; Organelles; Pancreas; Pancreatitis; Prognosis; Signal Transduction
PubMed: 30660726
DOI: 10.1053/j.gastro.2018.11.082 -
Nature Reviews. Cardiology Jun 2018
Topics: Alarmins; Atherosclerosis; Brain; Disease Progression; Humans; Stroke
PubMed: 29670205
DOI: 10.1038/s41569-018-0008-x -
European Respiratory Review : An... Mar 2023Interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) are alarmins that are released upon airway epithelial injury from insults such as viruses and cigarette... (Review)
Review
Interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) are alarmins that are released upon airway epithelial injury from insults such as viruses and cigarette smoke, and play critical roles in the activation of immune cell populations such as mast cells, eosinophils and group 2 innate lymphoid cells. Both cytokines were previously understood to primarily drive type 2 (T2) inflammation, but there is emerging evidence for a role for these alarmins to additionally mediate non-T2 inflammation, with recent clinical trial data in asthma and COPD cohorts with non-T2 inflammation providing support. Currently available treatments for both COPD and asthma provide symptomatic relief with disease control, improving lung function and reducing exacerbation rates; however, there still remains an unmet need for further improving lung function and reducing exacerbations, particularly for those not responsive to currently available treatments. The epithelial cytokines/alarmins are involved in exacerbations; biologics targeting TSLP and IL-33 have been shown to reduce exacerbations in moderate-to-severe asthma, either in a broad population or in specific subgroups, respectively. For COPD, while there is clinical evidence for IL-33 blockade impacting exacerbations in COPD, clinical data from anti-TSLP therapies is awaited. Clinical data to date support an acceptable safety profile for patients with airway diseases for both anti-IL-33 and anti-TSLP antibodies in development. We examine the roles of IL-33 and TSLP, their potential use as drug targets, and the evidence for target patient populations for COPD and asthma, together with ongoing and future trials focused on these targets.
Topics: Humans; Thymic Stromal Lymphopoietin; Immunity, Innate; Interleukin-33; Alarmins; Lymphocytes; Cytokines; Asthma; Inflammation; Lung; Pulmonary Disease, Chronic Obstructive
PubMed: 36697211
DOI: 10.1183/16000617.0144-2022 -
European Journal of Pharmacology Aug 2023Chronic stress affects millions of people around the world, and it can trigger different behavioral disorders like nociceptive hypersensitivity and anxiety, among...
Chronic stress affects millions of people around the world, and it can trigger different behavioral disorders like nociceptive hypersensitivity and anxiety, among others. However, the mechanisms underlaying these chronic stress-induced behavioral disorders have not been yet elucidated. This study was designed to understand the role of high-mobility group box-1 (HMGB1) and toll-like receptor 4 (TLR4) in chronic stress-induced nociceptive hypersensitivity. Chronic restraint stress induced bilateral tactile allodynia, anxiety-like behaviors, phosphorylation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) and activation of spinal microglia. Moreover, chronic stress enhanced HMGB1 and TLR4 protein expression at the dorsal root ganglion, but not at the spinal cord. Intrathecal injection of HMGB1 or TLR4 antagonists reduced tactile allodynia and anxiety-like behaviors induced by chronic stress. Additionally, deletion of TLR4 diminished the establishment of chronic stress-induced tactile allodynia in male and female mice. Lastly, the antiallodynic effect of HMGB1 and TLR4 antagonists were similar in stressed male and female rats and mice. Our results suggest that chronic restraint stress induces nociceptive hypersensitivity, anxiety-like behaviors, and up-regulation of spinal HMGB1 and TLR4 expression. Blockade of HMGB1 and TLR4 reverses chronic restraint stress-induced nociceptive hypersensitivity and anxiety-like behaviors and restores altered HMGB1 and TLR4 expression. The antiallodynic effects of HMGB1 and TLR4 blockers in this model are sex independent. TLR4 could be a potential pharmacological target for the treatment of the nociceptive hypersensitivity associated with widespread chronic pain.
Topics: Animals; Female; Male; Mice; Rats; Alarmins; Chronic Disease; HMGB1 Protein; Hyperalgesia; Nociception; p38 Mitogen-Activated Protein Kinases; Spinal Cord; Toll-Like Receptor 4
PubMed: 37244377
DOI: 10.1016/j.ejphar.2023.175804 -
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 -
The European Respiratory Journal Nov 2020Monoclonal antibody therapies have significantly improved treatment outcomes for patients with severe asthma; however, a significant disease burden remains. Available... (Review)
Review
Monoclonal antibody therapies have significantly improved treatment outcomes for patients with severe asthma; however, a significant disease burden remains. Available biologic treatments, including anti-immunoglobulin (Ig)E, anti-interleukin (IL)-5, anti-IL-5Rα and anti-IL-4Rα, reduce exacerbation rates in study populations by approximately 50% only. Furthermore, there are currently no effective treatments for patients with severe, type 2-low asthma. Existing biologics target immunological pathways that are downstream in the type 2 inflammatory cascade, which may explain why exacerbations are only partly abrogated. For example, type 2 airway inflammation results from several inflammatory signals in addition to IL-5. Clinically, this can be observed in how fractional exhaled nitric oxide ( ), which is driven by IL-13, may remain unchanged during anti-IL-5 treatment despite reduction in eosinophils, and how eosinophils may remain unchanged during anti-IL-4Rα treatment despite reduction in The broad inflammatory response involving cytokines including IL-4, IL-5 and IL-13 that ultimately results in the classic features of exacerbations (eosinophilic inflammation, mucus production and bronchospasm) is initiated by release of "alarmins" thymic stromal lymphopoietin (TSLP), IL-33 and IL-25 from the airway epithelium in response to triggers. The central, upstream role of these epithelial cytokines has identified them as strong potential therapeutic targets to prevent exacerbations and improve lung function in patients with type 2-high and type 2-low asthma. This article describes the effects of alarmins and discusses the potential role of anti-alarmins in the context of existing biologics. Clinical phenotypes of patients who may benefit from these treatments are also discussed, including how biomarkers may help identify potential responders.
Topics: Alarmins; Asthma; Biological Products; Cytokines; Eosinophils; Epithelium; Humans
PubMed: 32586879
DOI: 10.1183/13993003.00260-2020 -
Seminars in Immunology Aug 2018Alarmins are preformed, endogenous molecules that can be promptly released to signal cell or tissue stress or damage. The ubiquitous nuclear molecule high-mobility group... (Review)
Review
Alarmins are preformed, endogenous molecules that can be promptly released to signal cell or tissue stress or damage. The ubiquitous nuclear molecule high-mobility group box 1 protein (HMGB1) is a prototypical alarmin activating innate immunity. HMGB1 serves a dual alarmin function. The protein can be emitted to alert adjacent cells about endangered homeostasis of the HMGB1-releasing cell. In addition to this expected path of an alarmin, extracellular HMGB1 can be internalized via RAGE-receptor mediated endocytosis to the endolysosomal compartment while attached to other extracellular proinflammatory molecules. The endocytosed HMGB1 may subsequently destabilize lysosomal membranes. The HMGB1-bound partner molecules depend on the HMGB1-mediated transport and the induced lysosomal leakage to obtain access to endosomal and cytosolic reciprocal sensors to communicate extracellular threat and to initiate the proper activation pathways.
Topics: Alarmins; Animals; Extracellular Space; HMGB1 Protein; Homeostasis; Humans; Immunity, Innate; Inflammation; Intracellular Space
PubMed: 29530410
DOI: 10.1016/j.smim.2018.02.011 -
Neurobiology of Disease Jun 2022The distinction between glial painful and protective pathways is unclear and the possibility to finely modulate the system is lacking. Focusing on painful neuropathies,...
The distinction between glial painful and protective pathways is unclear and the possibility to finely modulate the system is lacking. Focusing on painful neuropathies, we studied the role of interleukin 1α (IL-1α), an alarmin belonging to the larger family of damage-associated molecular patterns endogenously secreted to restore homeostasis. The treatment of rat primary neurons with increasing doses of the neurotoxic anticancer drug oxaliplatin (0.3-100μM, 48 h) induced the release of IL-1α. The knockdown of the alarmin in neurons leads to their higher mortality when co-cultured with astrocytes. This toxicity was related to increased extracellular ATP and decreased release of transforming growth factor β1, mostly produced by astrocytes. In a rat model of neuropathy induced by oxaliplatin, the intrathecal treatment with IL-1α was able to reduce mechanical and thermal hypersensitivity both after acute injection (100 ng and 300 ng) and continuous infusion (100 and 300 ng/die). Ex vivo analysis on spinal purified astrocyte processes (gliosomes) and nerve terminals (synaptosomes) revealed the property of IL-1α to reduce the endogenous glutamate release induced by oxaliplatin. This protective effect paralleled with an increased number of GFAP-positive cells in the spinal cord, suggesting the ability of IL-1α to evoke a positive, conservative astrocyte phenotype. Endogenous IL-1α induced protective signals in the cross-talk between neurons and astrocytes. Exogenously administered in rats, IL-1α prevented neuropathic pain in the presence of spinal glutamate decrease and astrocyte activation.
Topics: Alarmins; Animals; Antineoplastic Agents; Astrocytes; Glutamic Acid; Hyperalgesia; Interleukin-1alpha; Neuralgia; Neurons; Oxaliplatin; Rats; Rats, Sprague-Dawley; Spinal Cord
PubMed: 35367629
DOI: 10.1016/j.nbd.2022.105716 -
Frontiers in Immunology 2021
Topics: Alarmins; Animals; Disease Susceptibility; Homeostasis; Host-Pathogen Interactions; Humans; Immunity; Plant Diseases; Plant Physiological Phenomena
PubMed: 35178047
DOI: 10.3389/fimmu.2021.844315 -
Nature Immunology Feb 2016Interleukin 33 (IL-33) is a member of the IL-1 family of cytokines with a growing number of target cells and a plethora of biological functions. Although it has... (Review)
Review
Interleukin 33 (IL-33) is a member of the IL-1 family of cytokines with a growing number of target cells and a plethora of biological functions. Although it has commonalities with other IL-1 cytokines, IL-33 exhibits some unique features. Here we review the biology of IL-33 and its receptor and develop a working model that describes two 'lives' for IL-33-one intracellular and one extracellular. Under healthy conditions, constitutively produced, intracellular IL-33 participates in maintaining barrier function by regulating gene expression as a nuclear protein. In parallel, nuclear IL-33 functions as a stored alarmin that is released when barriers are breached. Extracellular IL-33 coordinates immune defense and repair mechanisms while also initiating differentiation of helper T cells as the adaptive immune response is triggered.
Topics: Alarmins; Animals; Gene Expression Regulation; Humans; Inflammation; Interleukin-33; Protein Binding; Protein Transport; Receptors, Interleukin; Signal Transduction
PubMed: 26784265
DOI: 10.1038/ni.3370