DAMPs, PAMPs, and LAMPs in Immunity and Sterile Inflammation

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2019, Volume and Issue: 15(1), P. 493 - 518

Published: Nov. 1, 2019

Recognizing the importance of leukocyte trafficking in inflammation led to some therapeutic breakthroughs. However, many inflammatory pathologies remain without specific therapy. This review discusses leukocytes context sterile inflammation, a process caused by (non-microbial) molecules, comprising damage-associated molecular patterns (DAMPs). DAMPs bind receptors activate and start highly optimized sequence immune cell recruitment neutrophils monocytes initiate effective tissue repair. When are cleared, recruited change from proinflammatory reparative program, switch that is locally supervised invariant natural killer T cells. In addition, exit site reverse transmigrate back bloodstream. Inflammation persists when program or transmigration fails, coordinated effort cannot clear immunostimulatory molecules. The latter causes inappropriate activation, driver associated with poor lifestyle choices. We discuss lifestyle-associated diseases their corresponding (LAMPs) distinguish them DAMPs.

Language: Английский

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Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients

Proceedings of the National Academy of Sciences, Journal Year: 2020, Volume and Issue: 117(40), P. 25018 - 25025

Published: Sept. 17, 2020

Significance The new SARS-CoV-2 pandemic leads to COVID-19 with respiratory failure, substantial morbidity, and significant mortality. Overactivation of the innate immune response is postulated trigger this detrimental process. complement system a key player in immunity. Despite few reports local activation, there lack evidence that degree systemic activation occurs early patients, whether associated failure. This study shows number products are systemically, consistently, long-lastingly increased from admission during hospital stay. Notably, terminal sC5b-9 complex was Thus, inhibition an attractive therapeutic approach for treatment COVD-19.

Language: Английский

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Inflammasomes in Tissue Damages and Immune Disorders After Trauma

Frontiers in Immunology, Journal Year: 2018, Volume and Issue: 9

Published: Aug. 16, 2018

Trauma remains a leading cause of death worldwide. Hemorrhagic shock and direct injury to vital organs are responsible for early mortality whereas most delayed deaths secondary complex pathophysiological processes. These processes result from imbalanced systemic reactions the multiple aggressions associated with trauma. results in uncontrolled local release endogenous mediators acting as danger signals (damage-associated molecular patterns; DAMPs). Their recognition by innate immune system triggers pro-inflammatory response paradoxically concomitant immunosuppression. responses, ranging intensity inappropriate overwhelming, promote propagation injuries remote organs, organ failure death. Some numerous DAMPs released after trauma trigger assembly intracellular multiprotein complexes named inflammasomes. Once activated ligand, inflammasomes lead activation caspase. Activated caspases allow mature forms interleukin-1β interleukin-18 specific cell termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1 AIM2, involved generation tissue damage dysfunction Following trauma-induced DAMP(s) recognition, participate ways development exaggerated organ-specific inflammatory response, contributing damage. Inflammasomes responses traumatic brain contribute acute respiratory distress syndrome. may also play role post-trauma immunosuppression mediated dysregulated monocyte functions. Characterizing involvement pathogenesis syndrome is key issue they be potential adjuvant therapeutic targets. This review summarizes current knowledge on roles

Language: Английский

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Neuroinflammation after surgery: from mechanisms to therapeutic targets

Nature Immunology, Journal Year: 2020, Volume and Issue: 21(11), P. 1319 - 1326

Published: Oct. 19, 2020

Language: Английский

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Systemic Inflammatory Response Syndrome After Surgery: Mechanisms and Protection

Anesthesia & Analgesia, Journal Year: 2020, Volume and Issue: 131(6), P. 1693 - 1707

Published: Nov. 13, 2020

The immune system is an evolutionary hallmark of higher organisms that defends the host against invading pathogens and exogenous infections. This defense includes recruitment cells to site infection initiation inflammatory response contain eliminate pathogens. However, may also be triggered by noninfectious stimuli such as major surgery, and, in case overshooting, still not comprehensively understood reaction, lead tissue destruction organ dysfunction. Unfortunately, some cases, effectively distinguish between elicited which ideally should only require a modest response, those trauma or pathogenic infection. Surgical procedures thus represent potential trigger for systemic inflammation causes secretion proinflammatory cytokines, endothelial dysfunction, glycocalyx damage, activation neutrophils, ultimately multisystem destruction. In this review, we discuss summarize currently available mechanistic knowledge on surgery-associated inflammation, demarcation toward other complications, possible therapeutic options. These options depend uncovering underlying mechanisms could include pharmacologic agents, remote ischemic preconditioning protocols, cytokine blockade clearance, optimization surgical procedures, anesthetic regimens, perioperative diagnostic assessment. Currently, large gap basic science clinically confirmed data exists due limited evidence base translational studies. We important steps understanding precise time- space-regulated processes inflammation.

Language: Английский

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Damage-associated molecular patterns in trauma

European Journal of Trauma and Emergency Surgery, Journal Year: 2019, Volume and Issue: 46(4), P. 751 - 775

Published: Oct. 14, 2019

Abstract In 1994, the “danger model” argued that adaptive immune responses are driven rather by molecules released upon tissue damage than recognition of “strange” molecules. Thus, an alternative to “self versus non-self has been provided. The model, which suggests system discriminates dangerous from safe molecules, established basis for future designation damage-associated molecular patterns (DAMPs), a term was coined Walter G. Land, Seong, and Matzinger. pathological importance DAMPs is barely somewhere else evident as in posttraumatic or post-surgical inflammation regeneration. Since have identified trigger specific inflammation, not necessarily detrimental but also regenerative, it still remains difficult describe their “friend foe” role immunogenicity healing process. can be used biomarkers indicate and/or monitor disease injury severity, they may serve clinically applicable parameters optimized indication timing for, i.e., secondary surgeries. While experimental studies allow detection these on different levels including cellular, tissue, circulatory milieu, this always easily transferable human situation. review, we focus recent literature dealing with pathophysiological after traumatic injury. dysregulated traumatized patients implies disturbed resolution so-called model suppressing/inhibiting inducible (SAMPs) will very briefly introduced. update topic field trauma

Language: Английский

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Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

Pharmacological Reviews, Journal Year: 2021, Volume and Issue: 73(2), P. 792 - 827

Published: March 9, 2021

The complement system was discovered at the end of 19th century as a heat-labile plasma component that "complemented" antibodies in killing microbes, hence name "complement." Complement is also part innate immune system, protecting host by recognition pathogen-associated molecular patterns. However, multifunctional far beyond infectious defense. It contributes to organ development, such sculpting neuron synapses, promoting tissue regeneration and repair, rapidly engaging synergizing with number processes, including hemostasis leading thromboinflammation. double-edged sword. Although it usually protects host, may cause damage when dysregulated or overactivated, systemic inflammatory reaction seen trauma sepsis severe coronavirus disease 2019 (COVID-19). Damage-associated patterns generated during ischemia-reperfusion injuries (myocardial infarction, stroke, transplant dysfunction) chronic neurologic rheumatic activate complement, thereby increasing damaging inflammation. Despite long list diseases potential for ameliorating modulation, only few rare are approved clinical treatment targeting complement. Those currently being efficiently treated include paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome, myasthenia gravis, neuromyelitis optica spectrum disorders. Rare diseases, unfortunately, preclude robust trials. evidence pathogenetic driver many more common suggests an opportunity future therapy, which, however, requires trials; one ongoing example COVID-19 disease. current review aims discuss pathogenesis pharmacological strategies treat these complement-targeted therapies.

Significance Statement

host's defense friend from invading pathogens, maintaining homeostasis. sword, since overactivated becomes enemy, damage, failure, and, worst case, death. A acute candidates avoid complement-dependent ranging well established possible large patient groups like pandemic 2019.

Language: Английский

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Anti-Inflammatory and Immunoregulatory Action of Sesquiterpene Lactones

Molecules, Journal Year: 2022, Volume and Issue: 27(3), P. 1142 - 1142

Published: Feb. 8, 2022

Sesquiterpene lactones (SL), characterized by their high prevalence in the Asteraceae family, are one of major groups secondary metabolites found plants. Researchers from distinct research fields, including pharmacology, medicine, and agriculture, interested biological potential. With new SL discovered last years, activities have been tested, different action mechanisms (synergistic and/or antagonistic effects), as well molecular structure-activity relationships described. The review identifies main sesquiterpene with interconnections between immune responses anti-inflammatory actions, within cellular models vivo studies. Bioaccessibility bioavailability, addressed. Additionally, plant metabolic engineering, impact lactone extraction methodologies presented, perspective activity enhancement. derivatives also This summarizes current knowledge regarding therapeutic potential inflammatory activities, highlighting trends opportunities for pharmaceutical/clinical use.

Language: Английский

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DAMPs and radiation injury

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Jan. 25, 2024

The heightened risk of ionizing radiation exposure, stemming from accidents and potential acts terrorism, has spurred growing interests in devising effective countermeasures against injury. High-dose exposure triggers acute syndrome (ARS), manifesting as hematopoietic, gastrointestinal, neurovascular ARS. Hematopoietic ARS typically presents with neutropenia thrombocytopenia, while gastrointestinal results intestinal mucosal injury, often culminating lethal sepsis bleeding. This deleterious impact can be attributed to radiation-induced DNA damage oxidative stress, leading various forms cell death, such apoptosis, necrosis ferroptosis. Damage-associated molecular patterns (DAMPs) are intrinsic molecules released by cells undergoing injury or the process dying, either through passive active pathways. These then interact pattern recognition receptors, triggering inflammatory responses. Such a cascade events ultimately further tissue organ damage, contributing elevated mortality rate. Notably, infection develop cases, increasing release DAMPs. Given that stands major contributor ARS, DAMPs hold function mediators, exacerbating consequently worsening overall survival. review describes intricate mechanisms underlying Furthermore, it discusses detrimental effects on immune system explores DAMP-targeting therapeutic strategies alleviate

Language: Английский

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A conformational change of C-reactive protein drives neutrophil extracellular trap formation in inflammation

BMC Biology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 7, 2025

Abstract Background C-reactive protein (CRP) represents a routine diagnostic marker of inflammation. Dissociation native pentameric CRP (pCRP) into the monomeric structure (mCRP) liberates proinflammatory features, presumably contributing to excessive immune cell activation via unknown molecular mechanisms. Results In multi-translational study systemic inflammation, we found time- and inflammation-dependent pCRP dissociation mCRP. We were able confirm that mCRP co-localizes with leukocytes at site injury after polytrauma therefore assessed whether conformation potentiates neutrophil activation. mCRP-induced neutrophil-extracellular trap formation in vitro ex vivo involving nicotinamide adenine dinucleotide phosphate oxidase activation, p38/mitogen-activated kinase signaling, histone H3 citrullination. Mimicking trauma milieu human whole blood model, significant generation as well NET formation, prevented by blocking conformational changes. Conclusions Our data provide novel insights how contributes driver various inflammatory disorders.

Language: Английский

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