Mild acidosis delays neutrophil apoptosis via multiple signaling pathways and acts in concert with inflammatory mediators.
J Leukoc Biol
; 102(6): 1389-1400, 2017 12.
Article
en En
| MEDLINE
| ID: mdl-28928268
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
6_endocrine_disorders
/
6_other_blood_disorders
Asunto principal:
Acidosis
/
Transducción de Señal
/
Apoptosis
/
Mediadores de Inflamación
/
Neutrófilos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Leukoc Biol
Año:
2017
Tipo del documento:
Article