Neutrophil Extracellular Traps Promote the Development and Growth of Human Salivary Stones

Mantsopoulos, Konstantinos; Koch, Michael; Weidner, Daniela; Scholz, Michael; Wirtz, Stefan; Mahajan, Aparna; Herrmann, I; Singh, Jeeshan; Knopf, Jasmin; Leppkes, Moritz; Schauer, Christine; Grüneboom, Anika; Alexiou, Christoph; Schett, Georg; Iro, Heinrich; Muñoz, Luis E.; Herrmann, Martin

doi:10.3390/cells9092139

Cited by 32 publications

(43 citation statements)

References 72 publications

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“…At the very least, this study suggests that NETs initiate the formation and growth of sialoliths in humans. Deposition of extracellular DNA from neutrophil granulocytes around small crystals leads to their dense aggregation, and subsequent mineralization produces alternating dense mineral layers composed predominantly of calcium salt deposits and DNA [ 13 ]. Thus, further precipitation of calcium and other salivary components is triggered, and further stone growth is indicated.…”

Section: Discussionmentioning

confidence: 99%

“…The process of sialolith formation is still not fully understood, and different theories have been discussed [ 7 , 8 , 9 , 10 , 11 , 12 ]. Recently, neutrophil extracellular traps were reported to participate in sialolithogenesis, providing a promising explanation for salivary stone formation by uniting different theories in a common final path, which is based on an inflammatory process [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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The Translational Role of MUC8 in Salivary Glands: A Potential Biomarker for Salivary Stone Disease?

et al. 2021

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Mucin (MUC) 8 has been shown to play an important role in respiratory disease and inflammatory responses. In the present study, we investigated the question of whether MUC8 is also produced and secreted by salivary glands and whether it may also play a role in the oral cavity in the context of inflammatory processes or in the context of salivary stone formation. Tissue samples from parotid and submandibular glands of body donors (n = 6, age range 63–88 years), as well as surgically removed salivary stones from patients (n = 38, age range 48–72 years) with parotid and submandibular stone disease were immunohistochemically analyzed targeting MUC8 and TNFα. The presence of MUC8 in salivary stones was additionally analyzed by dot blot analyses. Moreover, saliva samples from patients (n = 10, age range 51–72 years), who had a salivary stone of the submandibular gland on one side were compared with saliva samples from the other “healthy” side, which did not have a salivary stone, by ELISA. Positive MUC8 was detectable in the inter- and intralobular excretory ducts of both glands (parotid and submandibular). The glandular acini showed no reactivity. TNFα revealed comparable reactivity to MUC8 in the glandular excretory ducts and also did not react in glandular acini. Salivary stones demonstrated a characteristic distribution pattern of MUC8 that differed between parotid and submandibular salivary stones. The mean MUC8 concentration was 71.06 ng/mL in female and 33.21 ng/mL in male subjects (p = 0.156). Saliva from the side with salivary calculi contained significantly (15-fold) higher MUC8 concentration levels than saliva from the healthy side (p = 0.0005). MUC8 concentration in salivary stones varied from 4.59 ng/mL to 202.83 ng/mL. In females, the MUC8 concentration in salivary stones was significantly (2.3-fold) higher, with an average of 82.84 ng/mL compared to 25.27 ng/mL in male patients (p = 0.034). MUC8 is secreted in the excretory duct system of salivary glands and released into saliva. Importantly, MUC8 salivary concentrations vary greatly between individuals. In addition, the MUC8 concentration is gender-dependent (♀️ > ♂). In the context of salivary stone diseases, MUC8 is highly secreted in saliva. The findings support a role for MUC8 in the context of inflammatory events and salivary stone formation. The findings allow conclusions on a gender-dependent component of MUC8.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Translational Role of MUC8 in Salivary Glands: A Potential Biomarker for Salivary Stone Disease?

et al. 2021

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“…Besides this beneficial, physiologic role, NETs and aggNETs reportedly also induce adverse effects. Indeed, NETs occlude Meibomian glands (11) and pancreatic ducts (12), promote formation and growth of gallstones (13) and salivary stones (14), and precipitate vasculopathy as well as immunothrombosis in COVID-19 (15). Furthermore, NETs may contribute to septic multi organ failure during tumor thrombosis (16)(17)(18) and malaria (19).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Promotes Neutrophil Survival After Acute Myocardial Infarction

et al. 2022

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Phagocytosis, degranulation, and neutrophil extracellular traps (NETs) formation build the armory of neutrophils for the first line of defense against invading pathogens. All these processes are modulated by the microenvironment including tonicity, pH and oxygen levels. Here we investigated the neutrophil infiltration in cardiac tissue autopsy samples of patients with acute myocardial infarction (AMI) and compared these with tissues from patients with sepsis, endocarditis, dermal inflammation, abscesses and diseases with prominent neutrophil infiltration. We observed many neutrophils infiltrating the heart muscle after myocardial infarction. Most of these had viable morphology and only few showed signs of nuclear de-condensation, a hallmark of early NET formation. The abundance of NETs was the lowest in acute myocardial infarction when compared to other examined diseases. Since cardiac oxygen supply is abruptly abrogated in acute myocardial infarction, we hypothesized that the resulting tissue hypoxia increased the longevity of the neutrophils. Indeed, the viable cells showed increased nuclear hypoxia inducible factor-1α (HIF-1α) content, and only neutrophils with low HIF-1α started the process of NET formation (chromatin de-condensation and nuclear swelling). Prolonged neutrophil survival, increased oxidative burst and reduced NETs formation were reproduced under low oxygen tensions and by HIF-1α stabilization in vitro. We conclude that nuclear HIF-1α is associated with prolonged neutrophil survival and enhanced oxidative stress in hypoxic areas of AMI.

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“…Recently, neutrophil recruitment and NETs formation in the salivary system were suggested to initiate sialolithiasis. Indeed, the demonstration of NE activity associated with a high prevalence of extracellular DNA points to NETs as nidi for the formation of sialoliths [ 104 ]. The high content of bicarbonate in saliva strengthens this hypothesis as it facilitates the formation of NETs [ 78 ].…”

Section: Occlusions Of Exocrine Glands and Ductsmentioning

confidence: 99%

Neutrophil Extracellular Trap-Driven Occlusive Diseases

Yaykaşlı

Schauer

Muñoz

et al. 2021

Cells

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The enlightenment of the formation of neutrophil extracellular traps (NETs) as a part of the innate immune system shed new insights into the pathologies of various diseases. The initial idea that NETs are a pivotal defense structure was gradually amended due to several deleterious effects in consecutive investigations. NETs formation is now considered a double-edged sword. The harmful effects are not limited to the induction of inflammation by NETs remnants but also include occlusions caused by aggregated NETs (aggNETs). The latter carries the risk of occluding tubular structures like vessels or ducts and appear to be associated with the pathologies of various diseases. In addition to life-threatening vascular clogging, other occlusions include painful stone formation in the biliary system, the kidneys, the prostate, and the appendix. AggNETs are also prone to occlude the ductal system of exocrine glands, as seen in ocular glands, salivary glands, and others. Last, but not least, they also clog the pancreatic ducts in a murine model of neutrophilia. In this regard, elucidating the mechanism of NETs-dependent occlusions is of crucial importance for the development of new therapeutic approaches. Therefore, the purpose of this review is to address the putative mechanisms of NETs-associated occlusions in the pathogenesis of disease, as well as prospective treatment modalities.

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Neutrophil Extracellular Traps Promote the Development and Growth of Human Salivary Stones

Cited by 32 publications

References 72 publications

The Translational Role of MUC8 in Salivary Glands: A Potential Biomarker for Salivary Stone Disease?

The Translational Role of MUC8 in Salivary Glands: A Potential Biomarker for Salivary Stone Disease?

Hypoxia Promotes Neutrophil Survival After Acute Myocardial Infarction

Neutrophil Extracellular Trap-Driven Occlusive Diseases

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