Extracellular pH Controls Chemotaxis of Neutrophil Granulocytes by Regulating Leukotriene B4 Production and Cdc42 Signaling

Oster, Leonie; Schröder, Julia; Rugi, Micol; Schimmelpfennig, Sandra; Sargin, Sarah; Schwab, Albrecht; Najder, Karolina

doi:10.4049/jimmunol.2100475

Cited by 9 publications

(8 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Superimposition of a chemical and a pH e gradient, as found at sites of inflammation, most efficiently stimulates NHE1-dependent, Cdc42-mediated directional migration of neutrophils [ 111 ]. Formylated peptides and complement molecule C5a, both secreted at the site of inflammation, induce neutrophil chemotaxis.…”

Section: Ph Taxis—directional Migration Along a Ph Gradientmentioning

confidence: 99%

“…The secretion of LTB 4 from activated neutrophils also depends on NHE1 activity and pH i and thus indirectly on pH e . It decreases with falling pH e and pH i or when NHE1 activity is inhibited [ 111 ]. NHE1 activity as a requirement for chemotaxis has been shown also for polymorphonuclear leukocytes in an fMLP gradient [ 127 ].…”

Section: Ph Taxis—directional Migration Along a Ph Gradientmentioning

confidence: 99%

“…At this point, the amplification mechanism comes into play to promote long-range chemotaxis and even allow cells to navigate mazes [ 170 ]. An almost perfect example for the role of acid extruders and pH e in “self-generated chemotaxis” is the above-mentioned NHE1, pH e , pH i , and Cdc42 dependence of directional neutrophil migration [ 111 ].…”

Section: Does Ph Contribute To Self-guidance Mechanisms?mentioning

confidence: 99%

“…Several cell types, even metabolically highly active tumor cells with generally upregulated net-acid extruding transporters compared with normal cells [ 42 ], e.g., human melanoma [ 161 ], lung carcinoma, and normal bronchial epithelial cells [ 146 ], rat prostate carcinoma cells [ 124 ], or neutrophils [ 67 , 111 ], respond to acidic pH e exposure by lowering their pH i values. Assuming that the intracellular acidification is a direct consequence of the extracellular acidification because (net) acid extruders such as NHEs and NBCs cannot work efficiently enough against the increasing extracellular proton concentration, the intracellular protons may act as messengers via cytosolic proteins with integrated molecular proton sensors, predominantly histidine and aspartate residues (see above).…”

Section: Acid Primingmentioning

confidence: 99%

“…Each of these mechanisms is one way or another related to, if not even directly dependent on, the pH value. While in the healing skin the migration of both fibroblasts and keratinocytes is most efficient at rather physiological pH values of around 7.5 [ 78 ], moderately acidic environments as found in tumor tissue or at inflammatory sites promote motility of tumor cells [ 121 , 155 ] and neutrophils [ 111 ], respectively. Aside from that, extracellular pH gradients direct migrating cells [ 114 , 166 ], and long-term exposure to relatively acidic pH values can cause cells to adopt a more migratory and invasive phenotype that can persist for hours up to several generations of cells after they have left the acidic milieu [ 123 , 163 ].…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

pH-regulated single cell migration

Stock

2024

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

Over the last two decades, extra- and intracellular pH have emerged as fundamental regulators of cell motility. Fundamental physiological and pathological processes relying on appropriate cell migration, such as embryonic development, wound healing, and a proper immune defense on the one hand, and autoimmune diseases, metastatic cancer, and the progression of certain parasitic diseases on the other, depend on surrounding pH. In addition, migrating single cells create their own localized pH nanodomains at their surface and in the cytosol. By this means, the migrating cells locally modulate their adhesion to, and the re-arrangement and digestion of, the extracellular matrix. At the same time, the cytosolic nanodomains tune cytoskeletal dynamics along the direction of movement resulting in concerted lamellipodia protrusion and rear end retraction. Extracellular pH gradients as found in wounds, inflamed tissues, or the periphery of tumors stimulate directed cell migration, and long-term exposure to acidic conditions can engender a more migratory and invasive phenotype persisting for hours up to several generations of cells after they have left the acidic milieu. In the present review, the different variants of pH-dependent single cell migration are described. The underlying pH-dependent molecular mechanisms such as conformational changes of adhesion molecules, matrix protease activity, actin (de-)polymerization, and signaling events are explained, and molecular pH sensors stimulated by H+ signaling are presented.

show abstract

Section: Ph Taxis—directional Migration Along a Ph Gradientmentioning

confidence: 99%

Section: Ph Taxis—directional Migration Along a Ph Gradientmentioning

confidence: 99%

Section: Does Ph Contribute To Self-guidance Mechanisms?mentioning

confidence: 99%

Section: Acid Primingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

pH-regulated single cell migration

Stock

2024

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

show abstract

Membrane potential dynamics of C5a-stimulated neutrophil granulocytes

Becker,

Swoboda,

Siemer

et al. 2024

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

Neutrophil granulocytes play a crucial role in host defense against invading pathogens and in inflammatory diseases. The aim of this study was to elucidate membrane potential dynamics during the initial phase of neutrophil activation and its relation to migration and production of reactive oxygen species (ROS). We performed ROS production measurements of neutrophils from healthy C57BL/6J mice after TNFα-priming and/or C5a stimulation. The actin cytoskeleton was visualized with fluorescence microscopy. Furthermore, we combined migration assays and measurements of membrane potential dynamics after stimulating unprimed and/or TNFα-primed neutrophils with C5a. We show that C5a has a concentration-dependent effect on ROS production and chemokinetic migration. Chemokinetic migration and chemotaxis are impaired at C5a concentrations that induce ROS production. The actin cytoskeleton of unstimulated and of ROS-producing neutrophils is not distributed in a polarized way. Inhibition of the phagocytic NADPH oxidase NOX2 with diphenyleneiodonium (DPI) leads to a polarized distribution of the actin cytoskeleton and rescues chemokinetic migration of primed and C5a-stimulated neutrophils. Moreover, C5a evokes a pronounced depolarization of the cell membrane potential by 86.6 ± 4.2 mV starting from a resting membrane potential of -74.3 ± 0.7 mV. The C5a-induced depolarization occurs almost instantaneously (within less than one minute) in contrast to the more gradually developing depolarization induced by PMA (lag time of 3—4 min). This initial depolarization is accompanied by a decrease of the migration velocity. Collectively, our results show that stimulation with C5a evokes parallel changes in membrane potential dynamics, neutrophil ROS production and motility. Notably, the amplitude of membrane potential dynamics is comparable to that of excitable cells.

show abstract

The influence of polarized membrane ion carriers and extracellular electrical/pH gradients on cell ionic homeostasis and locomotion

Li,

Sun

2023

Preprint

View full text Add to dashboard Cite

Anisotropic environmental signals or polarized membrane ion/solute carriers can generate spatially-varying intracellular gradients, leading to polarized cell dynamics. For example, directional migration of neutrophils, galvanotaxis of glioblastoma, and water flux in kidney cells, all result from the polarized distribution of membrane ion carriers and other intracellular components. The underlying physical mechanisms behind how polarized ion carriers interact with environmental signals are not well studied. Here, we use a physiologically-relevant, physics-based mathematical model to reveal how ion carriers generate intracellular ionic and voltage gradients. The model is able to discern the contribution of individual ion carriers to the intracellular pH gradient, electric potential, and water flux. We discover that an extracellular pH gradient leads to an intracellular pH gradient via chloride-bicarbonate exchangers, whereas an extracellular electric field leads to an intracellular electric potential gradient via passive potassium channels. In addition, the mechanical-biochemical coupling can modulate actin distribution and flow, and create biphasic dependence of the cell speed on water flux. Moreover, we find that F-actin interaction with NHE alone can generate cell movement, even when other ion carriers are not polarized. Taken together, the model shows the importance of cell ion dynamics in modulating cell migration and cytoskeletal dynamics.

show abstract

Extracellular pH Controls Chemotaxis of Neutrophil Granulocytes by Regulating Leukotriene B4 Production and Cdc42 Signaling

Cited by 9 publications

References 45 publications

pH-regulated single cell migration

pH-regulated single cell migration

Membrane potential dynamics of C5a-stimulated neutrophil granulocytes

The influence of polarized membrane ion carriers and extracellular electrical/pH gradients on cell ionic homeostasis and locomotion

Contact Info

Product

Resources

About