Extracellular acidosis induces neutrophil activation by a mechanism dependent on activation of phosphatidylinositol 3-kinase/Akt and ERK pathways

MARTINEZ D, , ; VERMEULEN M,; TREVANI A; CEBALLOS A; SABATTE J,; GAMBERALE R, ; ALVAREZ ME; SALAMONE G; COSO OA; GEFFNER J.

J Immunol

The American Association of Immunologists

Año: 2006 p. 1163 - 1671

Inflammation in peripheral tissues is usually associated with the development oflocal acidosis; however, there are few studies aimed at analyzing the influenceof acidosis on immune cells. We have shown previously that extracellularacidosis triggers human neutrophil activation, inducing a transient increase inintracellular Ca2+ concentration, a shape change response, the up-regulation ofCD18 expression, and a delay of apoptosis. In this study, we analyzed thesignaling pathways responsible for neutrophil activation. We found that acidosistriggers the phosphorylation of Akt (the main downstream target of PI3K) and ERKMAPK, but not that of p38 and JNK MAPK. No degradation of IkappaB was observed,supporting the hypothesis that NF-kappaB is not activated under acidosis.Inhibition of PI3K by wortmannin or LY294002 markedly decreased the shape changeresponse and the induction of Ca2+ transients triggered by acidosis, whereas theinhibition of MEK by PD98059 or U0126 significantly inhibited the shape changeresponse without affecting the induction of Ca2+ transients. We also found thatacidosis not only induces a shape change response and the induction of Ca2+transients in human neutrophils but also stimulates the endocytosis of FITC-OVAand FITC-dextran. Stimulation of endocytosis was partially prevented byinhibitors of PI3K and MEK. Together, our results support the notion that thestimulation of human neutrophils by extracellular acidosis is dependent on theactivation of PI3K/Akt and ERK pathways. Of note, using mouse peritonealneutrophils we observed that the enhancement of endocytosis induced by acidosiswas associated with an improved ability to present extracellular Ags through aMHC class I-restricted pathway.