Extracellular acidosis triggers the maturation of human dendritic cells and the production of IL-12.
Although the development of an acidic tissue environment or acidosis is a hallmark of inflammatory processes, few studies analyze the effect of extracellular pH on immune cells. We have previously shown that exposure of murine dendritic cells (DCs) to pH 6.5 stimulates macropinocytosis and cross-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 expression of HLA-DR, CD40, CD80, CD86, CD83, and CCR7 and improves the T cell priming ability of DCs. Incubation of DCs at pH 6.5 results in the activation of the PI3K/Akt and the MAPK pathways. Using specific inhibitors, we show that the maturation of DCs induced by acidosis was strictly dependent on the activation of p38 MAPK. DC exposure to pH 6.5 also induces a dramatic increase in their production of IL-12, stimulating the synthesis of IFN-gamma, but not IL-4, by Ag-specific CD4(+) T cells. Interestingly, we find that suboptimal doses of LPS abrogated the ability of pH 6.5 to induce DC maturation, suggesting a cross-talk between the activation pathways triggered by LPS and extracellular protons in DCs. We conclude that extracellular acidosis in peripheral tissues may contribute to the initiation of adaptive immune responses by DCs, favoring the development of Th1 immunity.
Martínez
Diego
D
Institute of Hematologic Research, National Academy of Medicine, National Reference Center for AIDS, and Department of Microbiology, Buenos Aires University School of Medicine, Argentina.
Vermeulen
Mónica
M
von Euw
Erika
E
Sabatté
Juan
J
Maggíni
Julian
J
Ceballos
Ana
A
Trevani
Analía
A
Nahmod
Karen
K
Salamone
Gabriela
G
Barrio
Marcela
M
Giordano
Mirta
M
Amigorena
Sebastian
S
Geffner
Jorge
J
D000138:Acidosis / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D045604:Extracellular Fluid / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D018664:Interleukin-12; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases