Extracellular acidosis triggers the maturation of human dendritic cells and the production of IL-12. J

DIEGO MARTÍNEZ, ; MÓNICA VERMEULEN; ERIKA VON EUW; ANALÍA TREVANI; ANA CEBALLOS; JUAN SABATTE; ROMINA GAMBERALE; MARÍA EUGENIA ÁLVAREZ; GABRIELA SALAMONE; TAMARA TANOS; OMAR COSO ; JORGE GEFFNER

JOURNAL OF IMMUNOLOGY

AMER ASSOC IMMUNOLOGISTS

Año: 2007 p. 1950 - 1959

0022-1767

Although the development of an acidic tissue environment or acidosis is ahallmark of inflammatory processes, few studies analyze the effect ofextracellular pH on immune cells. We have previously shown that exposure ofmurine dendritic cells (DCs) to pH 6.5 stimulates macropinocytosis andcross-presentation of extracellular Ags by MHC class I molecules. We report that the transient exposure of human DCs to pH 6.5 markedly increases the expressionof HLA-DR, CD40, CD80, CD86, CD83, and CCR7 and improves the T cell primingability of DCs. Incubation of DCs at pH 6.5 results in the activation of thePI3K/Akt and the MAPK pathways. Using specific inhibitors, we show that thematuration of DCs induced by acidosis was strictly dependent on the activation ofp38 MAPK. DC exposure to pH 6.5 also induces a dramatic increase in theirproduction of IL-12, stimulating the synthesis of IFN-gamma, but not IL-4, byAg-specific CD4(+) T cells. Interestingly, we find that suboptimal doses of LPSabrogated the ability of pH 6.5 to induce DC maturation, suggesting a cross-talk between the activation pathways triggered by LPS and extracellular protons inDCs. We conclude that extracellular acidosis in peripheral tissues may contributeto the initiation of adaptive immune responses by DCs, favoring the developmentof Th1 immunity.