Molecular regulation of neutrophil swarming in health and disease: Lessons from the phagocyte oxidase

Song, Zhimin; Bhattacharya, Sourav; Clemens, Regina A.; Dinauer, Mary C.

doi:10.1016/j.isci.2023.108034

Cited by 10 publications

(7 citation statements)

References 113 publications

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“…Neutrophil responses to chemoattractants are highly dependent on calcium (Ca 2+ ) entry [ 4 , 42 ]. Potentiation of [Ca 2+ ] c increase under the influence of fMLP is achieved through the launch of several signaling pathways.…”

Section: Resultsmentioning

confidence: 99%

“…Formylated peptide receptors (FPRs), namely FPR1 and FPR2, are abundantly expressed by neutrophils [ 3 ]. It is the signaling induced by formylated peptides of bacterial origin that ensures the early recruitment of neutrophils to the sites of pathogen invasion [ 4 ]. Among FPR1 agonists, N-formyl-methionyl-leucyl-phenylalanine (fMLP), a prototypic representative of bacterial chemotactic factor, has been identified as the most potent one [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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ATP and Formyl Peptides Facilitate Chemoattractant Leukotriene-B4 Synthesis and Drive Calcium Fluxes, Which May Contribute to Neutrophil Swarming at Sites of Cell Damage and Pathogens Invasion

Golenkina,

Viryasova,

Galkina

et al. 2024

Biomedicines

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Here, we demonstrate that human neutrophil interaction with the bacterium Salmonella typhimurium fuels leukotriene B4 synthesis induced by the chemoattractant fMLP. In this work, we found that extracellular ATP (eATP), the amount of which increases sharply during tissue damage, can effectively regulate fMLP-induced leukotriene B4 synthesis. The vector of influence strongly depends on the particular stage of sequential stimulation of neutrophils by bacteria and on the stage at which fMLP purinergic signaling occurs. Activation of 5-lipoxygenase (5-LOX), key enzyme of leukotriene biosynthesis, depends on an increase in the cytosolic concentration of Ca2+. We demonstrate that eATP treatment prior to fMLP, by markedly reducing the amplitude of the fMLP-induced Ca2+ transient jump, inhibits leukotriene synthesis. At the same time, when added with or shortly after fMLP, eATP effectively potentiates arachidonic acid metabolism, including by Ca2+ fluxes stimulation. Flufenamic acid, glibenclamide, and calmodulin antagonist R24571, all of which block calcium signaling in different ways, all suppressed 5-LOX product synthesis in our experimental model, indicating the dominance of calcium-mediated mechanisms in eATP regulatory potential. Investigation into the adhesive properties of neutrophils revealed the formation of cell clusters when adding fMLP to neutrophils exposed to the bacterium Salmonella typhimurium. eATP added simultaneously with fMLP supported neutrophil polarization and clustering. A cell-derived chemoattractant such as leukotriene B4 plays a crucial role in the recruitment of additional neutrophils to the foci of tissue damage or pathogen invasion, and eATP, through the dynamics of changes in [Ca2+]i, plays an important decisive role in fMLP-induced leukotrienes synthesis during neutrophil interactions with the bacterium Salmonella typhimurium.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ATP and Formyl Peptides Facilitate Chemoattractant Leukotriene-B4 Synthesis and Drive Calcium Fluxes, Which May Contribute to Neutrophil Swarming at Sites of Cell Damage and Pathogens Invasion

Golenkina,

Viryasova,

Galkina

et al. 2024

Biomedicines

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“… 67 However, neutrophils exhibit diverse inflammatory characteristics, including degranulation and release of inflammatory mediators, swarming, and aggregation with neighboring cells and tissues. 66 , 68 , 69 These tissue-toxic effects of neutrophils hinder the proper development of neutrophil-based delivery or cell therapies. Our integrated scRNA-seq and functional analyses identified a unique subset of neutrophils with potent homeostatic resolving capability enabled by TRAM reduction.…”

Section: Discussionmentioning

confidence: 99%

Resolving neutrophils through genetic deletion of TRAM attenuate atherosclerosis pathogenesis

Geng,

Zhang,

et al. 2024

iScience

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“…Early neutrophil recruitment is initiated by pathogen-associated molecular patterns (PAMPs), including N-formyl peptides, and damage-associated molecular patterns (DAMPs) ( 6 ). This interaction of “pioneer” neutrophils with pathogen (or danger signal from damaged tissue) results in leukotriene B4 (LTB4) synthesis, and started the next step, swam attractant release ( 7 ), leading to exponential accumulation of neutrophils at infection/damage loci ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

“…Leukotrienes play role also in inhibition of neutrophil swarming ( 6 ). ω-OH-LTB4 and ω-COOH-LTB4 compete with LTB4 for BLT1 receptor binding ( 11 ) and act as inhibitors of LTB4-mediated responses.…”

Section: Introductionmentioning

confidence: 99%

Redox processes are major regulators of leukotriene synthesis in neutrophils exposed to bacteria Salmonella typhimurium; the way to manipulate neutrophil swarming

Golenkina,

Viryasova,

Galkina

et al. 2024

Front. Immunol.

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Neutrophils play a primary role in protecting our body from pathogens. When confronted with invading bacteria, neutrophils begin to produce leukotriene B4, a potent chemoattractant that, in cooperation with the primary bacterial chemoattractant fMLP, stimulates the formation of swarms of neutrophils surrounding pathogens. Here we describe a complex redox regulation that either stimulates or inhibits fMLP-induced leukotriene synthesis in an experimental model of neutrophils interacting with Salmonella typhimurium. The scavenging of mitochondrial reactive oxygen species by mitochondria-targeted antioxidants MitoQ and SkQ1, as well as inhibition of their production by mitochondrial inhibitors, inhibit the synthesis of leukotrienes regardless of the cessation of oxidative phosphorylation. On the contrary, antioxidants N-acetylcysteine and sodium hydrosulfide promoting reductive shift in the reversible thiol-disulfide system stimulate the synthesis of leukotrienes. Diamide that oxidizes glutathione at high concentrations inhibits leukotriene synthesis, and the glutathione precursor S-adenosyl-L-methionine prevents this inhibition. Diamide-dependent inhibition is also prevented by diphenyleneiodonium, presumably through inhibition of NADPH oxidase and NADPH accumulation. Thus, during bacterial infection, maintaining the reduced state of glutathione in neutrophils plays a decisive role in the synthesis of leukotriene B4. Suppression of excess leukotriene synthesis is an effective strategy for treating various inflammatory pathologies. Our data suggest that the use of mitochondria-targeted antioxidants may be promising for this purpose, whereas known thiol-based antioxidants, such as N-acetylcysteine, may dangerously stimulate leukotriene synthesis by neutrophils during severe pathogenic infection.

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Molecular regulation of neutrophil swarming in health and disease: Lessons from the phagocyte oxidase

Cited by 10 publications

References 113 publications

ATP and Formyl Peptides Facilitate Chemoattractant Leukotriene-B4 Synthesis and Drive Calcium Fluxes, Which May Contribute to Neutrophil Swarming at Sites of Cell Damage and Pathogens Invasion

ATP and Formyl Peptides Facilitate Chemoattractant Leukotriene-B4 Synthesis and Drive Calcium Fluxes, Which May Contribute to Neutrophil Swarming at Sites of Cell Damage and Pathogens Invasion

Resolving neutrophils through genetic deletion of TRAM attenuate atherosclerosis pathogenesis

Redox processes are major regulators of leukotriene synthesis in neutrophils exposed to bacteria Salmonella typhimurium; the way to manipulate neutrophil swarming

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