The regulation of inflammation by oxidized phospholipids.
European Journal of Immunology 46(8):1818 (2016)
During inflammation or under conditions of oxidative stress, the polyunsaturated fatty acid side chains of phospholipids in cellular membranes or lipoproteins can be oxidatively modified. This process generates a complex mixture of structurally diverse oxidized phospholipid (OxPL) species, each ...
Total Synthesis of Prostaglandin 15d-PGJ(2) and Investigation of its Effect on the Secretion of IL-6 and IL-12.
Organic Letters 17(17):4340 (2015)
An efficient synthesis of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2, 1) is reported. The route described allows for diversification of the parent structure to prepare seven analogues of 1 in which the positioning of electrophilic sites is varied. These analogues were tested in SAR studies for t...
Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2.
Embo Molecular Medicine 7(5):593 (2015)
Exposure of biological membranes to reactive oxygen species creates a complex mixture of distinct oxidized phospholipid (OxPL) species, which contribute to the development of chronic inflammatory diseases and metabolic disorders. While the ability of OxPL to modulate biological processes is incr...
T cell lipid peroxidation induces ferroptosis and prevents immunity to infection.
Journal of Experimental Medicine 212(4):555 (2015)
The selenoenzyme glutathione peroxidase 4 (Gpx4) is a major scavenger of phospholipid hydroperoxides. Although Gpx4 represents a key component of the reactive oxygen species-scavenging network, its relevance in the immune system is yet to be defined. Here, we investigated the importance of Gpx4 ...
Discovery of a highly potent anti-inflammatory epoxyisoprostane-derived lactone.
Journal of the American Chemical Society 136(50):17382 (2014)
Epoxyisoprostanes EI (1) and EC (2) are effective inhibitors of the secretion of proinflammatory cytokines IL-6 and IL-12. In detailed studies toward the investigation of the molecular mode of action of these structures, a highly potent lactone (3) derived from 1 was identified. The known isopro...
Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1α and sterile vascular inflammation in atherosclerosis.
Nature Immunology 14(10):1045 (2013)
Chronic inflammation is a fundamental aspect of metabolic disorders such as obesity, diabetes and cardiovascular disease. Cholesterol crystals are metabolic signals that trigger sterile inflammation in atherosclerosis, presumably by activating inflammasomes for IL-1β production. We found here th...
Transport and uptake of immunogenic lipids.
Molecular Immunology 55(2):179 (2013)
An increasing number of lipid mediators have been identified as key modulators of immunity. Among these is a family of glycolipids capable of cellular uptake, loading onto the MHC-like molecule CD1d and stimulation of NKT cells. NKT cells are particularly interesting because they bridge innate a...
Synthesis of epoxyisoprostanes: effects in reducing secretion of pro-inflammatory cytokines IL-6 and IL-12.
Angewandte Chemie. International edition in Eng... 52(20):5382 (2013)
IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection.
PLoS Pathogens 9(5):e1003362 (2013)
Foxp3+ regulatory T (Treg) cells are essential for the maintenance of immune homeostasis and tolerance. During viral infections, Treg cells can limit the immunopathology resulting from excessive inflammation, yet potentially inhibit effective antiviral T cell responses and promote virus persiste...
Scavenger receptors target glycolipids for natural killer T cell activation.
Journal of Clinical Investigation 122(11):3943 (2012)
NKT cells are innate-like T cells with powerful regulatory functions that are a promising target for immunotherapy. The efficacy of glycolipids, such as the prototypic NKT cell antagonist α-galactosylceramide (αGalCer), is currently being evaluated in clinical trials, but little is known about f...
Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis.
European Journal of Immunology 41(7):2040 (2011)
Oxidative stress and inflammation--two components of the natural host response to injury--constitute important etiologic factors in atherogenesis. The pro-inflammatory cytokine interleukin (IL)-1 significantly enhances atherosclerosis, however, the molecular mechanisms of IL-1 induction within t...
Fatty acid amide hydrolase shapes NKT cell responses by influencing the serum transport of lipid antigen in mice.
Journal of Clinical Investigation 120(6):1873 (2010)
The potent regulatory properties of NKT cells render this subset of lipid-specific T cells a promising target for immunotherapeutic interventions. The marine sponge glycolipid alpha-galactosylceramide (alphaGalCer) is the proto-typic NKT cell agonist, which elicits this function when bound to CD...
Lysosomal recycling terminates CD1d-mediated presentation of short and polyunsaturated variants of the NKT cell lipid antigen alphaGalCer.
PNAS 106(25):10254 (2009)
Short or polyunsaturated lipid variants of the NKT cell antigen alpha-galactosylceramide (alphaGC) exhibit decreased potency and a Th2 bias in vivo despite conserved TCR contact residues and stable binding to CD1d at neutral and acidic pH. Using reagents to directly visualize lipids in their fre...
IL-21R on T cells is critical for sustained functionality and control of chronic viral infection.
Science 324(5934):1576 (2009)
Chronic viral infection is often associated with the dysfunction of virus-specific T cells. Our studies using Il21r-deficient (Il21r-/-) mice now suggest that interleukin-21 (IL-21) is critical for the long-term maintenance and functionality of CD8+ T cells and the control of chronic lymphocytic...
Synthesis of diglycosylceramides and evaluation of their iNKT cell stimulatory properties.
Bioorganic & Medicinal Chemistry Letters 18(10):3052 (2008)
Stimulation of iNKT cells is highly dependent on the structures of the glycolipids presented by CD1d. Furthermore, antigen processing and CD1d loading in lysosomes play central roles in controlling the stimulatory properties of glycolipid antigens. Previously, we determined that substitution at ...
Corrugoside, a new immunostimulatory alpha-galactoglycosphingolipid from the marine sponge Axinella corrugata.
Bioorganic & Medicinal Chemistry 16(4):2077 (2008)
Corrugoside (1a), a new immunostimulatory triglycosilated alpha-galactoglycosphingolipid, was isolated from the marine sponge Axinella corrugata, and its structure determined by spectral analysis and chemical degradation. Compound 1a activated murine NKT cells in vitro, with a potency of about 2...
Corrugoside, a new immunostimulatory α-galactoglycosphingolipid from the marine spongeAxinella corrugata
Bioorganic & Medicinal Chemistry 16(4):2077 (2008)
Developmental programming: maternal hypercholesterolemia and immunity influence susceptibility to atherosclerosis.
Nutrition Reviews 65(12 Pt 2):S182 (2007)
It is increasingly recognized that the in utero environment is an important determinant of adult disease, and extensive epidemiological evidence links dysmetabolic conditions during pregnancy with increased hypertension, cardiovascular disease, and diabetes later in life. The original Barker Hyp...
Extralymphatic virus sanctuaries as a consequence of potent T-cell activation.
Nature Medicine 13(11):1316 (2007)
T helper cells can support the functions of CD8(+) T cells against persistently infecting viruses such as murine lymphocytic choriomeningitis virus (LCMV), cytomegalovirus, hepatitis C virus and HIV. These viruses often resist complete elimination and remain detectable at sanctuary sites, such a...
A lymphocytic choriomeningitis virus glycoprotein variant that is retained in the endoplasmic reticulum efficiently cross-primes CD8(+) T cell responses.
PNAS 104(33):13426 (2007)
Recent studies indicate that T cell cross-priming preferentially occurs against long-lived, stable proteins. We have studied cross-priming by using the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), a protein that normally is not MHC class I cross-presented. This study shows tha...