| Autor: |
Martin-Gutierrez, Lucia, Waddington, Kirsty E, Maggio, Annalisa, Coelewij, Leda, Oppong, Alexandra E, Yang, Nina, Adriani, Marsilio, Nytrova, Petra, Farrell, Rachel, Pineda-Torra, Inés, Jury, Elizabeth C |
| Předmět: |
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| Zdroj: |
Clinical & Experimental Immunology; Aug2024, Vol. 217 Issue 2, p204-218, 15p |
| Abstrakt: |
Altered cholesterol, oxysterol, sphingolipid, and fatty acid concentrations are reported in blood, cerebrospinal fluid, and brain tissue of people with relapsing-remitting multiple sclerosis (RRMS) and are linked to disease progression and treatment responses. CD4 + T cells are pathogenic in RRMS, and defective T-cell function could be mediated in part by liver X receptors (LXRs)—nuclear receptors that regulate lipid homeostasis and immunity. RNA-sequencing and pathway analysis identified that genes within the 'lipid metabolism' and 'signalling of nuclear receptors' pathways were dysregulated in CD4 + T cells isolated from RRMS patients compared with healthy donors. While LXRB and genes associated with cholesterol metabolism were upregulated, other T-cell LXR-target genes, including genes involved in cellular lipid uptake (inducible degrader of the LDL receptor, IDOL), and the rate-limiting enzyme for glycosphingolipid biosynthesis (UDP-glucosylceramide synthase, UGCG) were downregulated in T cells from patients with RRMS compared to healthy donors. Correspondingly, plasma membrane glycosphingolipids were reduced, and cholesterol levels increased in RRMS CD4 + T cells, an effect partially recapitulated in healthy T cells by in vitro culture with T-cell receptor stimulation in the presence of serum from RRMS patients. Notably, stimulation with LXR-agonist GW3965 normalized membrane cholesterol levels, and reduced proliferation and IL17 cytokine production in RRMS CD4 + T-cells. Thus, LXR-mediated lipid metabolism pathways were dysregulated in T cells from patients with RRMS and could contribute to RRMS pathogenesis. Therapies that modify lipid metabolism could help restore immune cell function. Lipid metabolism was dysregulated in CD4 + T cells and serum from patients with relapsing-remitting multiple sclerosis compared to healthy controls, characterized by differential regulation of genes involved in cellular lipid uptake and lipid biosynthesis, altered T-cell plasma membrane lipid profiles and changes in serum lipoprotein expression. Alterations in T-cell plasma membrane lipids (lipid rafts) could be partially recapitulated in healthy T cells by in vitro culture with T-cell receptor stimulation in the presence of serum from RRMS patients. Conversely, co-stimulation of RRMS T cells with a liver X receptor (LXR)-agonist (a nuclear receptor important for lipid homeostasis), normalized membrane cholesterol levels, and reduced proliferation and IL17 cytokine production, suggesting that defects in LXR-mediated lipid metabolism pathways could contribute to RRMS pathogenesis. Graphical Abstract [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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