The Fatal Circle of NETs and NET-Associated DAMPs Contributing to Organ Dysfunction

Block, Helena; Rossaint, Jan; Zarbock, Alexander

doi:10.3390/cells11121919

Cited by 39 publications

(30 citation statements)

References 242 publications

(269 reference statements)

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“…However, excessive formation of NETs may mediate exaggerated inflammatory immune responses perpetuating the release of inflammatory cytokines. This may contribute to a cascade of DAMPs-NETs-cytokines mediated persistent inflammation, sepsis, MODS, and death in polytrauma patients [ 54 , 55 ] and thus DAMPs-induced NETs activation ( Figure 1 ) should be an interesting area of research to improve clinical outcomes in polytrauma patients. This notion is further supported by the findings of NETs as one potential source of circulating cell-free DNA (cfDNA) which contributes to post-trauma inflammation and coagulation regulation [ 56 ].…”

Section: Damps Sirs and Traumamentioning

confidence: 99%

Translational and Clinical Significance of DAMPs, PAMPs, and PRRs in Trauma-induced Inflammation

Rai¹,

Mathews²,

Agrawal³

2022

Arch Clin Biomed Res

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Increased morbidity and mortality after polytrauma due to multiple organ failure (MOF) is a major concern for clinicians. Systemic inflammatory response syndrome (SIRS) and sepsis are the major underlying causes. Damage-associated molecular proteins (DAMPs) released after polytrauma induce an inflammatory immune response to repair the tissue, however, persistent inflammation finally results in immunosuppression and MOF. During immunosuppression, additional exposure of the traumatized tissue to pattern-associated molecular patterns (PAMPs) further adds to the continuum of inflammatory cascade causing sepsis. These two hits worsen the condition of the patient and increase morbidity and mortality. Thus, it is critical to stratify the patient based on trauma severity and inflammatory biomarkers levels and design treatment accordingly for a better clinical outcome. Although some of the molecular mechanisms involved in SIRS and MOF after polytrauma have been reported, there is limited information on the critical factors related to the study of DAMPs and PAMPs, including the timing of sampling (time elapsed after trauma), source of sampling (blood, urine, saliva), proteomics and metabolomics, multiplex plasma assay, comparative interpretation of the results from various sources and diagnostic value, and interpretation on the translational and clinical significance. Additionally, there is limited literature on DAMPs like heat shock proteins, mitochondrial DNA, neutrophil extracellular traps, and their role in SIRS and MOF. Further, it is also important to distinguish between the biomarkers of SIRS and sepsis in a time-bound window to have a better clinical outcome. This critical review focuses on these aspects to provide comprehensive information and thought-provoking discussion to design future investigation and clinical trials.

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Section: Damps Sirs and Traumamentioning

confidence: 99%

Translational and Clinical Significance of DAMPs, PAMPs, and PRRs in Trauma-induced Inflammation

Rai¹,

Mathews²,

Agrawal³

2022

Arch Clin Biomed Res

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“…High-mobility group box 1 protein (HMGB1) is a well-known DAMP that received its name from its high mobility in polyacrylamide gel electrophoresis [ 106 , 107 ]. In 2006, Yasuda et al discovered a link between serum HMGB1 levels and disease severity in SAP patients.…”

Section: Exosome-specific Proteinsmentioning

confidence: 99%

Fighting Fire with Fire: Exosomes and Acute Pancreatitis-Associated Acute Lung Injury

et al. 2022

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Acute pancreatitis (AP) is a prevalent clinical condition of the digestive system, with a growing frequency each year. Approximately 20% of patients suffer from severe acute pancreatitis (SAP) with local consequences and multi-organ failure, putting a significant strain on patients’ health insurance. According to reports, the lungs are particularly susceptible to SAP. Acute respiratory distress syndrome, a severe type of acute lung injury (ALI), is the primary cause of mortality among AP patients. Controlling the mortality associated with SAP requires an understanding of the etiology of AP-associated ALI, the discovery of biomarkers for the early detection of ALI, and the identification of potentially effective drug treatments. Exosomes are a class of extracellular vesicles with a diameter of 30–150 nm that are actively released into tissue fluids to mediate biological functions. Exosomes are laden with bioactive cargo, such as lipids, proteins, DNA, and RNA. During the initial stages of AP, acinar cell-derived exosomes suppress forkhead box protein O1 expression, resulting in M1 macrophage polarization. Similarly, macrophage-derived exosomes activate inflammatory pathways within endothelium or epithelial cells, promoting an inflammatory cascade response. On the other hand, a part of exosome cargo performs tissue repair and anti-inflammatory actions and inhibits the cytokine storm during AP. Other reviews have detailed the function of exosomes in the development of AP, chronic pancreatitis, and autoimmune pancreatitis. The discoveries involving exosomes at the intersection of AP and acute lung injury (ALI) are reviewed here. Furthermore, we discuss the therapeutic potential of exosomes in AP and associated ALI. With the continuous improvement of technological tools, the research on exosomes has gradually shifted from basic to clinical applications. Several exosome-specific non-coding RNAs and proteins can be used as novel molecular markers to assist in the diagnosis and prognosis of AP and associated ALI.

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“…Additionally, neutrophil death releases DNA and proteases. All of these act as DAMPs and disseminate innate immunity activation [ 30 ].…”

Section: Circulating Immune Cellsmentioning

confidence: 99%

“…The formation of NETs may undergo either lytic/suicidal or non-lytic/vital pathway [ 30 ]. Lytic NETosis is induced by most known pathogens, including viruses, and results in cell membrane breakage and death.…”

Section: Programmed Cell Death In Akimentioning

confidence: 99%

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Update on Innate Immunity in Acute Kidney Injury—Lessons Taken from COVID-19

Musiał

2022

IJMS

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The serious clinical course of SARS-CoV-2 infection is usually accompanied by acute kidney injury (AKI), worsening prognosis and increasing mortality. AKI in COVID-19 is above all a consequence of systemic dysregulations leading to inflammation, thrombosis, vascular endothelial damage and necrosis. All these processes rely on the interactions between innate immunity elements, including circulating blood cells, resident renal cells, their cytokine products, complement systems, coagulation cascades and contact systems. Numerous simultaneous pathways of innate immunity should secure an effective host defense. Since they all form a network of cross-linked auto-amplification loops, uncontrolled activation is possible. When the actions of selected pathways amplify, cascade activation evades control and the propagation of inflammation and necrosis worsens, accompanied by complement overactivity and immunothrombosis. The systemic activation of innate immunity reaches the kidney, where the damage affecting single tubular cells spreads through tissue collateral damage and triggers AKI. This review is an attempt to synthetize the connections between innate immunity components engaged in COVID-19-related AKI and to summarize the knowledge on the pathophysiological background of processes responsible for renal damage.

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The Fatal Circle of NETs and NET-Associated DAMPs Contributing to Organ Dysfunction

Cited by 39 publications

References 242 publications

Translational and Clinical Significance of DAMPs, PAMPs, and PRRs in Trauma-induced Inflammation

Translational and Clinical Significance of DAMPs, PAMPs, and PRRs in Trauma-induced Inflammation

Fighting Fire with Fire: Exosomes and Acute Pancreatitis-Associated Acute Lung Injury

Update on Innate Immunity in Acute Kidney Injury—Lessons Taken from COVID-19

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