Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients.
Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft-associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor β (LXRβ), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+ T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE.
Georgia
G
McDonald
Shantal
S
Deepak
Laura
L
Miguel
Cleo J
CJ
Hall
David A
DA
Isenberg
Anthony I
AI
Magee
Terry
T
Butters
Elizabeth C
EC
Jury
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000737:chemistry; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000737:chemistry; D001402:B-Lymphocytes / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D005260:Female; D005434:Flow Cytometry; D005677:G(M1) Ganglioside / Q000737:chemistry; D005786:Gene Expression Regulation; D006028:Glycosphingolipids / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007790:Lactosylceramides / Q000737:chemistry; D007963:Leukocytes, Mononuclear / Q000166:cytology; D000071518:Liver X Receptors; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000188:drug therapy / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D021962:Membrane Microdomains / Q000737:chemistry; D008875:Middle Aged; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014281:Trihexosylceramides / Q000737:chemistry
D015703:Antigens, CD; D006028:Glycosphingolipids; D007790:Lactosylceramides; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D014281:Trihexosylceramides; D017485:1-Deoxynojirimycin; D005677:G(M1) Ganglioside; C009744:CDw17 antigen; C018549:globotriaosylceramide; C059896:miglustat