Mild acidosis delays neutrophil apoptosis and enhances pro-survival signals from inflammatory mediators

Abstract

Abstract Emerging evidence indicates that local acidosis associated with infection and tissue injury triggers innate and adaptive immunity. Activation of infiltrating neutrophils contributes to transient drop in pH. We investigated the impact of extracellular acidosis on neutrophil apoptosis, one of the check points in the outcome of the inflammatory response, and on the survival signals generated by bacterial DNA and serum amyloid A. Culture of human isolated neutrophils under mild acidosis (pH 6.5–7.0) resulted in concurrent activation of NF-κB, adenyl cyclase and the ERK and PI3K/Akt signaling pathways, leading to preservation of Mcl-1. Consequently, extracellular acidosis prevented disruption of mitochondrial transmembrane potential and translocation of cytochrome c, endonuclease G and apoptosis-inducing factor (AIF) from the mitochondria to cytoplasm and nuclei, respectively and attenuated activation of caspase-3. Pharmacological inhibition of ERK, PI3K, NF-κB and adenylcyclase partially reversed the anti-apoptotic action of acidosis. Furthermore, mild acidosis enhanced the pro-survival signal from bacterial DNA and serum amyloid A by enhancing ERK and PI3K-mediated inhibition of Mcl-1 degradation. Our results identify mild acidosis as a survival signal for neutrophils by suppressing the constitutive apoptotic machinery and suggest that transient decreases in local pH could contribute to amplification of inflammation. Funding Support: Supported by grants from CIHR (MOP-97742).