Extracellular Acidosis Induces Neutrophil Activation by a Mechanism Dependent on Activation of Phosphatidylinositol 3-Kinase/Akt and ERK Pathways

MARTÍNEZ, D.; VERMEULEN, M.; TREVANI, A. S.; CEBALLOS, A.; SABATTÉ, J.; GAMBERALE, R.; ÁLVAREZ, M. E.; SALAMONE, G.; TANOS, T.; COSO, O. A.; GEFFNER, J. R.

JOURNAL OF IMMUNOLOGY

Año: 2006 p. 1163 - 1171

0022-1767

AbstractInflammation in peripheral tissues is usually associated with the development of local acidosis; however, there are few studiesaimed at analyzing the influence of acidosis on immune cells. We have shown previously that extracellular acidosis triggers humanneutrophil activation, inducing a transient increase in intracellular Ca2 concentration, a shape change response, the up-regulationof CD18 expression, and a delay of apoptosis. In this study, we analyzed the signaling pathways responsible for neutrophilactivation. We found that acidosis triggers the phosphorylation of Akt (the main downstream target of PI3K) and ERK MAPK,but not that of p38 and JNK MAPK. No degradation of IB was observed, supporting the hypothesis that NF-B is not activatedunder acidosis. Inhibition of PI3K by wortmannin or LY294002 markedly decreased the shape change response and the inductionof Ca2 transients triggered by acidosis, whereas the inhibition of MEK by PD98059 or U0126 significantly inhibited the shapechange response without affecting the induction of Ca2 transients. We also found that acidosis not only induces a shape changeresponse and the induction of Ca2 transients in human neutrophils but also stimulates the endocytosis of FITC-OVA andFITC-dextran. Stimulation of endocytosis was partially prevented by inhibitors of PI3K and MEK. Together, our results supportthe notion that the stimulation of human neutrophils by extracellular acidosis is dependent on the activation of PI3K/Akt and ERKpathways. Of note, using mouse peritoneal neutrophils we observed that the enhancement of endocytosis induced by acidosis wasassociated with an improved ability to present extracellular Ags through a MHC class I-restricted pathway. The Journal ofImmunology, 2006, 176: 1163–1171.