Self-Glycolipids Modulate Dendritic Cells Changing the Cytokine Profiles of Committed Autoreactive T Cells

Buschard, Karsten; Månsson, Jan‐Eric; Roep, Bart O.; Nikolić, Tatjana

doi:10.1371/journal.pone.0052639

Cited by 7 publications

(6 citation statements)

References 40 publications

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“…These effects were independent of CD1d, a known receptor for sulfatides, and were partially mediated by L-selectin, which was shown to bind to sulfatide in leukocytes (23). Data also point to C24-sulfatide activation of TLR4-and TLR2dependent signaling in human dendritic cells (24), while another report provides evidence that long FA chain sulfatides block LPSstimulated localization of TLR4 within lipid rafts and activation of NF-κB and MAP kinases in RAW264.7 macrophages, and prevent LPS-induced acute lethality in mice (25). Thus, the role of sulfatides in inflammation and specifically in TLR binding/activation remains poorly defined.…”

mentioning

confidence: 83%

Sulfatides are endogenous ligands for the TLR4–MD-2 complex

Athamna

Wang

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Many endogenous molecules, mostly proteins, purportedly activate the Toll-like receptor 4 (TLR4)–myeloid differentiation factor-2 (MD-2) complex, the innate immune receptor for lipopolysaccharide (LPS) derived from gram-negative bacteria. However, there is no structural evidence supporting direct TLR4–MD-2 activation by endogenous ligands. Sulfatides (3-O-sulfogalactosylceramides) are natural, abundant sulfated glycolipids that have variously been shown to initiate or suppress inflammatory responses. We show here that short fatty acid (FA) chain sulfatides directly activate mouse TLR4–MD-2 independent of CD14, trigger MyD88- and TRIF-dependent signaling, and stimulate tumor necrosis factor α (TNFα) and type I interferon (IFN) production in mouse macrophages. In contrast to the agonist activity toward the mouse receptor, the tested sulfatides antagonize TLR4–MD-2 activation by LPS in human macrophage-like cells. The agonistic and antagonistic activities of sulfatides require the presence of the sulfate group and are inversely related to the FA chain length. The crystal structure of mouse TLR4–MD-2 in complex with C16-sulfatide revealed that three C16-sulfatide molecules bound to the MD-2 hydrophobic pocket and induced an active dimer conformation of the receptor complex similar to that induced by LPS or lipid A. The three C16-sulfatide molecules partially mimicked the detailed interactions of lipid A to achieve receptor activation. Our results suggest that sulfatides may mediate sterile inflammation or suppress LPS-stimulated inflammation, and that additional endogenous negatively charged lipids with up to six lipid chains of limited length might also bind to TLR4–MD-2 and activate or inhibit this complex.

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mentioning

confidence: 83%

Sulfatides are endogenous ligands for the TLR4–MD-2 complex

Athamna

Wang

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…LDL and HDL bind the lipid metabolite βGlcCer (65,66). Lipid metabolites regulate DC differentiation/function (26)(27)(28)(29), and DCs mediate initiation of allergic disease (4,12). It is reported that βGalCer is required for hematopoiesis (67) and that ceramide is elevated in allergic non-pregnant female mice (68).…”

Section: Discussionmentioning

confidence: 99%

“…Concentrations of some lipid metabolites are altered during allergic inflammation in humans and mice (20)(21)(22)(23)(24)(25). Lipid metabolites regulate DC differentiation/function (26)(27)(28)(29) and DCs mediate initiation of allergic disease (4,12). Furthermore, maternal lipids (30)(31)(32) are also present in milk and may regulate development of the immune system in the neonate.…”

Section: Introductionmentioning

confidence: 99%

β-Glucosylceramide From Allergic Mothers Enhances Offspring Responsiveness to Allergen

et al. 2021

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In animals and humans, offspring of allergic mothers have increased responsiveness to allergen and the allergen-specificity of the offspring can be different than that of the mother. In our preclinical models, the mother's allergic responses influence development of the fetus and offspring by elevating numbers of cells in dendritic cell subsets. A major question is the identity of maternal factors of allergic mothers that alter offspring development of responsiveness to allergen. Lipids are altered during allergic responses and lipids are transported to the fetus for growth and formation of fetal membranes. We hypothesized that pro-inflammatory lipids, that are elevated in allergic mothers, are transported to the fetus and regulate fetal immune development. We demonstrate in this report that there was a significant 2-fold increase in β-glucosylceramides (βGlcCer) in allergic mothers, the fetal liver and her offspring. The βGlcCer were transported from mother's plasma, across the placenta, to the fetus and in breastmilk to the offspring. Administration of βGlcCer to non-allergic mothers was sufficient for offspring responses to allergen. Importantly, maternal administration of a clinically relevant pharmacological inhibitor of βGlcCer synthase returned βGlcCer to normal levels in the allergic mothers and her offspring and blocked the offspring increase in dendritic cell subsets and offspring allergen responsiveness. In summary, allergic mothers had increased βGlcCer that was transported to offspring and mediated increases in offspring DCs and responsiveness to allergen. These data have a significant impact on our understanding of mechanisms for development of allergies in offspring of allergic mothers and have the potential to lead to novel interventions that significantly impact risk for allergic disease early in life.

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“…Prenatal PM 2.5 air pollutant exposure referred to period averages from measures taken from each trimester on the basis of temporally and spatially resolved, aerosolized optical depth data. 37 For consistency, these variables were also included in multivariable models with the FVC percent predicted outcome. All models with child 3-year tocopherols were also adjusted for some hemolysis, which occurred in 22% of the samples because lipids are released from cell membranes during hemolysis.…”

Section: Discussionmentioning

confidence: 99%

Associations of α- and γ-tocopherol during early life with lung function in childhood

Kumar

Ferrie

Balmert

et al. 2020

Journal of Allergy and Clinical Immunology

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Background: Tocopherol isoforms may regulate child lung growth and spirometric measures. Objective: Our aim was to determine the extent to which plasma a-tocopherol (a-T) or g-tocopherol (g-T) isoform levels in early childhood or in utero are associated with childhood lung function. Methods: We included 622 participants in the Project Viva cohort who had lung function at a mid-childhood visit (age 6-10 years). Maternal and child tocopherol isoform levels were measured by HPLC at the second trimester and 3 years of age, respectively. Multivariable linear regression models (adjusted for mid-childhood body mass index z scores, maternal education, smoking in pregnancy, and prenatal particulate matter with diameter of <2.5 micrometers (PM 2.5) particulate exposure) stratified by tertiles of child g-T level were used to assess the association of aT levels with FEV 1 and forced vital capacity (FVC) percent predicted. Similarly, models stratified by child aT tertile evaluated associations of g-T levels with lung function. We performed similar analyses with maternal second trimester tocopherol isoform levels. Results: The median maternal second trimester aT level was 63 mM (interquartile range 5 47-82). The median early-childhood level was 25 mM (interquartile range 5 20-33 mM). In the lowest tertile of early-childhood g-T, children with a higher aT level (per 10 mM) had a higher mid-childhood FEV 1 percent predicted (b 5 3.09; 95% CI 5 0.58-5.59 and a higher FVC percent predicted (b 5 2.77; 95% CI 5 0.47-5.06). This protective association of aT was lost at higher g-T levels. We did not see any consistent associations of second trimester levels of either aT or g-T with mid-childhood FEV 1 or FVC. Conclusion: When g-T levels were in the lowest tertile, a higher early-childhood aT level was associated with better lung function at mid-childhood. Second trimester maternal plasma aT concentration was 3-fold higher than in the adult nonpregnant female population.

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Self-Glycolipids Modulate Dendritic Cells Changing the Cytokine Profiles of Committed Autoreactive T Cells

Cited by 7 publications

References 40 publications

Sulfatides are endogenous ligands for the TLR4–MD-2 complex

Sulfatides are endogenous ligands for the TLR4–MD-2 complex

β-Glucosylceramide From Allergic Mothers Enhances Offspring Responsiveness to Allergen

Associations of α- and γ-tocopherol during early life with lung function in childhood

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