Physiological and Pathophysiological Roles of Metabolic Pathways for NET Formation and Other Neutrophil Functions

Stojkov, Darko; Gigon, Lea; Peng, Shuang; Łukowski, Robert; Ruth, Peter; Караулов, А. В.; Rizvanov, Albert A.; Barlev, Nickolai A.; Yousefi, Shída; Simon, Hans‐Uwe

doi:10.3389/fimmu.2022.826515

Cited by 26 publications

(31 citation statements)

References 228 publications

(386 reference statements)

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“…These cells respond rapidly to infection and injury in various tissues. They represent the first line of defense and utilize multiple mechanisms of oxygen-dependent and oxygen-independent processes to protect against infection, including phagocytosis, cytokine secretion, and reactive oxygen species production [ 60 , 61 ]. Thus, neutrophils represent a potential target for the development of novel anti-inflammatory therapeutics.…”

Section: Resultsmentioning

confidence: 99%

Neutrophil Immunomodulatory Activity of Farnesene, a Component of Artemisia dracunculus Essential Oils

Schepetkin

Özek

et al. 2022

Pharmaceuticals

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Despite their reported therapeutic properties, not much is known about the immunomodulatory activity of essential oils present in Artemisia species. We isolated essential oils from the flowers and leaves of five Artemisia species: A. tridentata, A. ludoviciana, A. dracunculus, A. frigida, and A. cana. The chemical composition of the Artemisia essential oil samples had similarities and differences as compared to those previously reported in the literature. The main components of essential oils obtained from A. tridentata, A. ludoviciana, A. frigida, and A. cana were camphor (23.0–51.3%), 1,8-cineole (5.7–30.0%), camphene (1.6–7.7%), borneol (2.3–14.6%), artemisiole (1.2–7.5%), terpinen-4-ol (2.0–6.9%), α-pinene (0.8–3.9%), and santolinatriene (0.7–3.5%). Essential oils from A. dracunculus were enriched in methyl chavicol (38.8–42.9%), methyl eugenol (26.1–26.4%), terpinolene (5.5–8.8%), (E/Z)-β-ocimene (7.3–16.0%), β-phellandrene (1.3–2.2%), p-cymen-8-ol (0.9–2.3%), and xanthoxylin (1.2–2.2%). A comparison across species also demonstrated that some compounds were present in only one Artemisia species. Although Artemisia essential oils were weak activators of human neutrophils, they were relatively more potent in inhibiting subsequent neutrophil Ca2+ mobilization with N-formyl peptide receptor 1 (FPR1) agonist fMLF- and FPR2 agonist WKYMVM, with the most potent being essential oils from A. dracunculus. Further analysis of unique compounds found in A. dracunculus showed that farnesene, a compound with a similar hydrocarbon structure as lipoxin A4, inhibited Ca2+ influx induced in human neutrophils by fMLF (IC50 = 1.2 μM), WKYMVM (IC50 = 1.4 μM), or interleukin 8 (IC50 = 2.6 μM). Pretreatment with A. dracunculus essential oils and farnesene also inhibited human neutrophil chemotaxis induced by fMLF, suggesting these treatments down-regulated human neutrophil responses to inflammatory chemoattractants. Thus, our studies have identified farnesene as a potential anti-inflammatory modulator of human neutrophils.

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Section: Resultsmentioning

confidence: 99%

Neutrophil Immunomodulatory Activity of Farnesene, a Component of Artemisia dracunculus Essential Oils

Schepetkin

Özek

et al. 2022

Pharmaceuticals

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“…Neutrophils are the most abundant leukocyte and are vital for innate immunity [ 55 ]. These cells are the first responders to infection and injury in various tissues, establishing the first line of defense through multiple mechanisms such as phagocytosis, cytokine secretion, and reactive oxygen species production [ 56 , 57 ]. Thus, neutrophils represent an ideal pharmacological target for therapeutic development, and numerous natural products, including essential oils, have been shown to exhibit neutrophil immunomodulatory activity [ 29 , 30 , 31 , 32 , 33 ].…”

Section: Resultsmentioning

confidence: 99%

Neutrophil Immunomodulatory Activity of (−)-Borneol, a Major Component of Essential Oils Extracted from Grindelia squarrosa

Schepetkin

Özek

et al. 2022

Molecules

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Grindelia squarrosa (Pursh) Dunal is used in traditional medicine for treating various diseases; however, little is known about the immunomodulatory activity of essential oils from this plant. Thus, we isolated essential oils from the flowers (GEOFl) and leaves (GEOLv) of G. squarrosa and evaluated the chemical composition and innate immunomodulatory activity of these essential oils. Compositional analysis of these essential oils revealed that the main components were α-pinene (24.7 and 23.2% in GEOFl and GEOLv, respectively), limonene (10.0 and 14.7%), borneol (23.4 and 16.6%), p-cymen-8-ol (6.1 and 5.8%), β-pinene (4.0 and 3.8%), bornyl acetate (3.0 and 5.1%), trans-pinocarveol (4.2 and 3.7%), spathulenol (3.0 and 2.0%), myrtenol (2.5 and 1.7%), and terpinolene (1.7 and 2.0%). Enantiomer analysis showed that α-pinene, β-pinene, and borneol were present primarily as (−)-enantiomers (100% enantiomeric excess (ee) for (−)-α-pinene and (−)-borneol in both GEOFl and GEOLv; 82 and 78% ee for (−)-β-pinene in GEOFl and GEOLv), while limonene was present primarily as the (+)-enantiomer (94 and 96 ee in GEOFl and GEOLv). Grindelia essential oils activated human neutrophils, resulting in increased [Ca2+]i (EC50 = 22.3 µg/mL for GEOFl and 19.4 µg/mL for GEOLv). In addition, one of the major enantiomeric components, (−)-borneol, activated human neutrophil [Ca2+]i (EC50 = 28.7 ± 2.6), whereas (+)-borneol was inactive. Since these treatments activated neutrophils, we also evaluated if they were able to down-regulate neutrophil responses to subsequent agonist activation and found that treatment with Grindelia essential oils inhibited activation of these cells by the N-formyl peptide receptor 1 (FPR1) agonist fMLF and the FPR2 agonist WKYMVM. Likewise, (−)-borneol inhibited FPR-agonist-induced Ca2+ influx in neutrophils. Grindelia leaf and flower essential oils, as well as (−)-borneol, also inhibited fMLF-induced chemotaxis of human neutrophils (IC50 = 4.1 ± 0.8 µg/mL, 5.0 ± 1.6 µg/mL, and 5.8 ± 1.4 µM, respectively). Thus, we identified (−)-borneol as a novel modulator of human neutrophil function.

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“…Both mitochondrial [ 265 , 266 ] and nuclear DNA [ 262 ] have been found to form or at least make up parts of NETs. As reviewed elsewhere [ 267 , 268 , 269 ], the details of the different pathways involved in NET formation is still rather controversial and highly debated. With this in mind, we briefly describe what is known to date about the mechanisms of formation ( Figure 6 ).…”

Section: Other Sources Of Cell-free Dnamentioning

confidence: 99%

“…In 2009 Yousefi et al demonstrated that NETs from viable neutrophils can also be composed of mtDNA. Two modes of mitochondrial NET formation/extrusion have been suggested so far: (a) mtDNA may be released into cytosol where it is further packed into vesicles and released by fusion with the plasma membrane thereby forming traps [ 275 ]; (b) The direct release of mtDNA and granules in a catapult-like manner via fusion of the mitochondrial and plasma membrane [ 269 , 271 , 275 ].…”

Section: Other Sources Of Cell-free Dnamentioning

confidence: 99%

New Perspectives on the Importance of Cell-Free DNA Biology

et al. 2022

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Body fluids are constantly replenished with a population of genetically diverse cell-free DNA (cfDNA) fragments, representing a vast reservoir of information reflecting real-time changes in the host and metagenome. As many body fluids can be collected non-invasively in a one-off and serial fashion, this reservoir can be tapped to develop assays for the diagnosis, prognosis, and monitoring of wide-ranging pathologies, such as solid tumors, fetal genetic abnormalities, rejected organ transplants, infections, and potentially many others. The translation of cfDNA research into useful clinical tests is gaining momentum, with recent progress being driven by rapidly evolving preanalytical and analytical procedures, integrated bioinformatics, and machine learning algorithms. Yet, despite these spectacular advances, cfDNA remains a very challenging analyte due to its immense heterogeneity and fluctuation in vivo. It is increasingly recognized that high-fidelity reconstruction of the information stored in cfDNA, and in turn the development of tests that are fit for clinical roll-out, requires a much deeper understanding of both the physico-chemical features of cfDNA and the biological, physiological, lifestyle, and environmental factors that modulate it. This is a daunting task, but with significant upsides. In this review we showed how expanded knowledge on cfDNA biology and faithful reverse-engineering of cfDNA samples promises to (i) augment the sensitivity and specificity of existing cfDNA assays; (ii) expand the repertoire of disease-specific cfDNA markers, thereby leading to the development of increasingly powerful assays; (iii) reshape personal molecular medicine; and (iv) have an unprecedented impact on genetics research.

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Physiological and Pathophysiological Roles of Metabolic Pathways for NET Formation and Other Neutrophil Functions

Cited by 26 publications

References 228 publications

Neutrophil Immunomodulatory Activity of Farnesene, a Component of Artemisia dracunculus Essential Oils

Neutrophil Immunomodulatory Activity of Farnesene, a Component of Artemisia dracunculus Essential Oils

Neutrophil Immunomodulatory Activity of (−)-Borneol, a Major Component of Essential Oils Extracted from Grindelia squarrosa

New Perspectives on the Importance of Cell-Free DNA Biology

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