title: Extracellular acidosis induces neutrophil activation by a mechanism dependent on activation of phosphatidylinositol 3-kinase/Akt and ERK pathways.
abstract: Inflammation in peripheral tissues is usually associated with the development of local acidosis; however, there are few studies aimed at analyzing the influence of acidosis on immune cells. We have shown previously that extracellular acidosis triggers human neutrophil activation, inducing a transient increase in intracellular Ca2+ concentration, a shape change response, the up-regulation of CD18 expression, and a delay of apoptosis. In this study, we analyzed the signaling pathways responsible for neutrophil activation. 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 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 change response and the induction of Ca2+ transients triggered by acidosis, whereas the inhibition of MEK by PD98059 or U0126 significantly inhibited the shape change response without affecting the induction of Ca2+ transients. We also found that acidosis not only induces a shape change response and the induction of Ca2+ transients in human neutrophils but also stimulates the endocytosis of FITC-OVA and FITC-dextran. Stimulation of endocytosis was partially prevented by inhibitors of PI3K and MEK. Together, our results support the notion that the stimulation of human neutrophils by extracellular acidosis is dependent on the activation of PI3K/Akt and ERK pathways. Of note, using mouse peritoneal neutrophils we observed that the enhancement of endocytosis induced by acidosis was associated with an improved ability to present extracellular Ags through a MHC class I-restricted pathway.
authors.affiliation: Institute of Hematologic Research, National Academy of Medicine and National Reference Center for AIDS, Department of Microbiology, Buenos Aires University School of Medicine, Buenos Aires, Argentina.
authors.forename: Diego
authors.initials: D
authors.lastname: Martínez
authors.forename: Mónica
authors.initials: M
authors.lastname: Vermeulen
authors.forename: Analía
authors.initials: A
authors.lastname: Trevani
authors.forename: Ana
authors.initials: A
authors.lastname: Ceballos
authors.forename: Juan
authors.initials: J
authors.lastname: Sabatté
authors.forename: Romina
authors.initials: R
authors.lastname: Gamberale
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: Alvarez
authors.forename: Gabriela
authors.initials: G
authors.lastname: Salamone
authors.forename: Tamara
authors.initials: T
authors.lastname: Tanos
authors.forename: Omar A
authors.initials: OA
authors.lastname: Coso
authors.forename: Jorge
authors.initials: J
authors.lastname: Geffner
mesh_terms: D000138:Acidosis / Q000276:immunology*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017951:Antigen Presentation; D020013:Calcium Signaling; D048430:Cell Shape; D004705:Endocytosis; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects / Q000502:physiology*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D015395:Histocompatibility Antigens Class I; D048031:JNK Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one