Extracellular Acidification Acts as a Key Modulator of Neutrophil Apoptosis and Functions

Cao, Shengnan; Liu, Peng; Zhu, Haiyan; Gong, Haiyan; Sun, Yawei; Geng, Guangfeng; Wang, Tong; Feng, Sizhou; Han, Mingzhe; Zhou, Jiaxi; Xu, Yuanfu

doi:10.1371/journal.pone.0137221

Cited by 31 publications

(31 citation statements)

References 45 publications

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“…The stimulatory effects of conventional agonists were markedly increased by a low pH and the neutrophils responded with more production of H 2 O 2 and increased release of myeloperoxidase (13). A more recent publication confirms these results, indicating that a pH of 6.0 prolongs neutrophil survival and increases phagocytosis of bacteria; however, phagolysosomal killing is decreased (14). Neutrophils cultivated in alkaline conditions show decreased survival compared to neutral or acidic environments (15).…”

Section: Discussionmentioning

confidence: 78%

“…The importance of the choice of the acidifying agent is highlighted by findings showing that hydrochloric acid induces an inflammatory response in stimulated RAW 264.7 cells, whereas acidification with lactate leads to an anti-inflammatory phenotype (17). However, the buffering agent is not solely responsible for the diverse effects reported through the years as indicated by inconsistent results even among studies using one and the same buffering system (13, 14, 16, 18). …”

Section: Discussionmentioning

confidence: 99%

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Ménage-à-Trois: The Ratio of Bicarbonate to CO2 and the pH Regulate the Capacity of Neutrophils to Form NETs

et al. 2016

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In this study, we identified and characterized the potential of a high ratio of bicarbonate to CO2 and a moderately alkaline pH to render neutrophils prone to undergo neutrophil extracellular trap (NET) formation. Both experimental settings increased the rate of spontaneous NET release and potentiated the NET-inducing capacity of phorbol esters (phorbol-2-myristate-13-acetate), ionomycin, monosodium urate, and LPS. In contrast, an acidic environment impaired NET formation both spontaneous and induced. Our findings indicate that intracellular alkalinization of neutrophils in response to an alkaline environment leads to an increase of intracellular calcium and neutrophil activation. We further found that the anion channel blocker DIDS strongly reduced NET formation induced by bicarbonate. This finding suggests that the effects observed are due to a molecular program that renders neutrophils susceptible to NET formation. Inflammatory foci may be characterized by an acidic environment. Our data indicate that NET formation is favored by the higher pH at the border regions of inflamed areas. Moreover, our findings highlight the necessity for strict pH control during assays of NET formation.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Ménage-à-Trois: The Ratio of Bicarbonate to CO2 and the pH Regulate the Capacity of Neutrophils to Form NETs

et al. 2016

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“…Furthermore, e.c. acidification prolongs the neutrophil survival, ROS production is inhibited, and phagocytosis is increased, but phagolysosomal killing is decreased …”

Section: Resultsmentioning

confidence: 99%

“…acidification prolongs the neutrophil survival, ROS production is inhibited, and phagocytosis is increased, but phagolysosomal killing is decreased. 56 On the basis of these observations, we consider that neutrophils are highly sensitive cells that execute different activation programs depending on the environment they encounter. On the one hand, the…”

Section: The Functional Shift Of Neutrophils After Eye Openingmentioning

confidence: 99%

Frontline Science: Aggregated neutrophil extracellular traps prevent inflammation on the neutrophil-rich ocular surface

Mahajan

Grüneboom

Petrů

et al. 2019

Journal of Leukocyte Biology

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Eye rheum is a physiological discharge, which accumulates at the medial angle of the healthy eye soon after opening in the morning. Microscopic evaluation of eye rheum revealed the presence of viable neutrophils, bacteria, epithelial cells, and particles, aggregated by neutrophil extracellular traps. We observed that in the evening, during eye closure, high C5a recruited neutrophils to the tear film and activated them. In this hypoxic area rich in CO2, neutrophils fight microbial aggressors by degranulation. Immediately after eye opening, the microenvironment of the ocular surface changes, the milieu gets normoxic, and loss of CO2 induces subtle alkalinization of tear film. These conditions favored the formation of neutrophil extracellular traps (NETs) that initially covers the ocular surface and tend to aggregate by eyelid blinking. These aggregated neutrophil extracellular traps (aggNETs) are known as eye rheum and contain several viable neutrophils, epithelial cells, dust particles, and crystals packed together by NETs. Similar to aggNETs induced by monosodium urate crystals, the eye rheum shows a robust proteolytic activity that degraded inflammatory mediators before clinically overt inflammation occur. Finally, the eye rheum passively floats with the tear flow to the medial angle of the eye for disposal. We conclude that the aggNETs‐based eye rheum promotes cleaning of the ocular surface and ameliorates the inflammation on the neutrophil‐rich ocular surfaces.

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“…In neutrophils, extracellular acidosis induces shape change [29], releases PAF [30], upregulates surface expression of CD18 [29], enhances endocytosis and improves presentation of extracellular Ags through a MHC class I-restricted pathway [31] through activation of the PI3K/Akt, ERK 1/2 [31], and p38 MAPK pathways [30]. Extracellular acidification also leads to inhibition of superoxide generation [32,33] and the formation of neutrophil extracellular traps [34]. Delayed neutrophil apoptosis has also been noted in acidotic media [29,33].…”

Section: Introductionmentioning

confidence: 99%

Mild acidosis delays neutrophil apoptosis via multiple signaling pathways and acts in concert with inflammatory mediators

Kebir

Santos

Mansouri

et al. 2017

Journal of Leukocyte Biology

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Accumulating evidence indicates development of local extracellular acidosis in inflamed tissues in response to infection and tissue injury. Activation of infiltrating neutrophils contributes to a transient decrease in pH, which, in turn, triggers innate immunity. In this study, we investigated the impact of extracellular acidosis on neutrophil apoptosis, a critical determinant of the outcome of the inflammatory response and analyzed the underlying signaling pathways. Culture of human isolated neutrophils in mildly acidotic conditions (pH 6.5-7.0) resulted in activation of NF-κB; intracellular accumulation of cAMP; and phosphorylation of Akt, ERK, and p38 MAPK; and preservation of Mcl-1 expression. Consequently, extracellular acidosis prevented disruption of mitochondrial transmembrane potential and translocation of cytochrome and apoptosis-inducing factor from the mitochondria to cytoplasm and nuclei, respectively and inhibited caspase-3 activity. Pharmacological inhibition of ERK, PI3K, NF-κB, or PKA partially reversed survival cues by extracellular acidosis and redirected neutrophils to apoptosis. Conversely, dibutyryl cAMP (100-500 μM) delayed apoptosis of neutrophils cultured at pH 7.4. Extracellular acidosis-generated survival cues were additive to the potent prosurvival signals from bacterial DNA, LPS, modified C-reactive protein, and serum amyloid A. Acidosis increased CpG DNA uptake by neutrophils and augmented phosphorylation of ERK and Akt, leading to preservation of Mcl-1 expression. Our results identified extracellular acidosis as a survival signal for neutrophils by suppressing the constitutive apoptotic machinery and suggest that transient decreases in local pH can enhance neutrophil responses to inflammatory stimuli, thereby contributing to amplification or prolongation of the inflammatory response.

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Extracellular Acidification Acts as a Key Modulator of Neutrophil Apoptosis and Functions

Cited by 31 publications

References 45 publications

Ménage-à-Trois: The Ratio of Bicarbonate to CO2 and the pH Regulate the Capacity of Neutrophils to Form NETs

Ménage-à-Trois: The Ratio of Bicarbonate to CO2 and the pH Regulate the Capacity of Neutrophils to Form NETs

Frontline Science: Aggregated neutrophil extracellular traps prevent inflammation on the neutrophil-rich ocular surface

Mild acidosis delays neutrophil apoptosis via multiple signaling pathways and acts in concert with inflammatory mediators

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