Mild acidosis delays neutrophil apoptosis via multiple signaling pathways and acts in concert with inflammatory mediators
Bibliographic record
Abstract
Abstract 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 c 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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".