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Mild acidosis delays neutrophil apoptosis
Author(s) -
El Kebir Driss,
Jozsef Levente,
Pan Wanling,
Wang Lili,
Filep Janos G.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.38.8
Subject(s) - acidosis , apoptosis , inflammation , kinase , extracellular , cytochrome c , protein kinase b , cytosol , mapk/erk pathway , microbiology and biotechnology , biology , immunology , endocrinology , biochemistry , enzyme
Emerging evidence indicates that local acidosis associated with infection and inflammation 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, a critical determinant of the outcome of the inflammatory responses. Culture of human isolated neutrophils under mild acidosis (pH 6.0–7.0) resulted in concurrent activation of the ERK and PI3‐kinase/Akt signaling pathways, leading to phosphorylation of the pro‐apoptotic protein BAD at Ser112 and Ser136, respectively and prevention of the degradation of Mcl‐1. Consequently, extracellular acidosis prevented disruption of mitochondrial transmembrane potential and translocation of cytochrome c to the cytosol from the mitochondria. Acidosis produced similar delay in apoptosis that could be achieved with LPS. Pharmacological inhibition of either ERK or phosphatidylinositol 3‐kinase partially reversed the anti‐apoptotic action of acidosis. 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 prolongation and amplification of inflammation. (Supported by CIHR MOP‐97742).