Uncoupling between CD1d upregulation induced by retinoic acid and conduritol-B-epoxide and iNKT cell responsiveness.
Gaucher disease (GD) is associated with upregulation of CD1d and MHC-class II expression by monocytes. While the physiological impact of CD1d upregulation remains uncertain, it has been proposed that MHC-class II upregulation is associated with inflammation. Hereby, we show that the decrease in MHC-class II expression seen in GD patients under therapy correlates positively with chitotriosidase activity, a marker of inflamed macrophages. We also show that retinoic acid (RA) and the beta-glucocerebrosidase inhibitor conduritol-B-epoxide (CBE) lead to upregulation of CD1d expression by THP-1 cells, which correlated with an increase in mRNA expression. In vitro co-culture experiments showed that RA treated THP-1 cells were more stimulatory for CD4(+) than for CD8(+) T cells, as determined by CFSE loss, in comparison to untreated THP-1 cells. Interestingly, even though addition of exogenous isoglobotrihexosylceramide (iGb3), a physiological CD1d ligand, augmented the percentage of dividing CD4(+) T cells, we could not detect a significant expansion of CD4(+)Valpha24(+) invariant Natural Killer T (iNKT) cells. In contrast, addition of alpha-galactosylceramide (alpha-GC) induced expansion of Valpha24(+) iNKT cells as determined by using alpha-GC-loaded human CD1d dimers. These results strengthen the existence of a cross-talk between monocyte lipid accumulation, inflammation and changes in cell surface CD1d and MHC-class II in monocytes, which may result in inappropriate recognition events by immune cells and perpetuate chronic inflammation.
Balreira
Andrea
A
IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal.
Cavallari
Marco
M
Sá Miranda
Maria Clara
MC
Arosa
Fernando A
FA
D055610:Antigens, CD1d / Q000096:biosynthesis / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002908:Chronic Disease; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005776:Gaucher Disease / Q000276:immunology / Q000378:metabolism; D005915:Globosides / Q000494:pharmacology; D006596:Hexosaminidases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007249:Inflammation; D007294:Inositol / Q000031:analogs & derivatives* / Q000494:pharmacology; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000276:immunology; D014212:Tretinoin / Q000494:pharmacology*; D014281:Trihexosylceramides / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects* / Q000276:immunology
D055610:Antigens, CD1d; D000970:Antineoplastic Agents; C526877:CD1D protein, human; D004791:Enzyme Inhibitors; D005915:Globosides; D000949:Histocompatibility Antigens Class II; D012333:RNA, Messenger; D014281:Trihexosylceramides; C514781:isoglobotrihexosylceramide; D007294:Inositol; D014212:Tretinoin; D006596:Hexosaminidases; C086400:chitotriosidase; C011423:conduritol epoxide