TY  - JOUR
A1  - Sic, Heiko
A1  - Kraus, Helene
A1  - Madl, Josef
A1  - Flittner, Karl-Andreas
A1  - von Muenchow, Audrey Lilly
A1  - Pieper, Kathrin
A1  - Rizzi, Marta
A1  - Kienzler, Anne-Kathrin
A1  - Ayata, Korcan
A1  - Rauer, Sebastian
A1  - Kleuser, Burkhard
A1  - Salzer, Ulrich
A1  - Burger, Meike
A1  - Zirlik, Katja
A1  - Lougaris, Vassilios
A1  - Plebani, Alessandro
A1  - Roemer, Winfried
A1  - Loeffler, Christoph
A1  - Scaramuzza, Samantha
A1  - Villa, Anna
A1  - Noguchi, Emiko
A1  - Grimbacher, Bodo
A1  - Eibel, Hermann
T1  - Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis
JF  - The journal of allergy and clinical immunology
N2  - Background: Five different G protein-coupled sphingosine-1-phosphate (S1P) receptors (S1P1-S1P5) regulate a variety of physiologic and pathophysiologic processes, including lymphocyte circulation, multiple sclerosis (MS), and cancer. Although B-lymphocyte circulation plays an important role in these processes and is essential for normal immune responses, little is known about S1P receptors in human B cells.
 Objective: To explore their function and signaling, we studied B-cell lines and primary B cells from control subjects, patients with leukemia, patients with S1P receptor inhibitor-treated MS, and patients with primary immunodeficiencies.
 Methods: S1P receptor expression was analyzed by using multicolor immunofluorescence microscopy and quantitative PCR. Transwell assays were used to study cell migration. S1P receptor internalization was visualized by means of time-lapse imaging with fluorescent S1P receptor fusion proteins expressed by using lentiviral gene transfer. B-lymphocyte subsets were characterized by means of flow cytometry and immunofluorescence microscopy.
 Results: Showing that different B-cell populations express different combinations of S1P receptors, we found that S1P1 promotes migration, whereas S1P4 modulates and S1P2 inhibits S1P1 signals. Expression of CD69 in activated B lymphocytes and B cells from patients with chronic lymphocytic leukemia inhibited S1P-induced migration. Studying B-cell lines, normal B lymphocytes, and B cells from patients with primary immunodeficiencies, we identified Bruton tyrosine kinase, beta-arrestin 2, LPS-responsive beige-like anchor protein, dedicator of cytokinesis 8, and Wiskott-Aldrich syndrome protein as critical signaling components downstream of S1P1.
 Conclusion: Thus S1P receptor signaling regulates human B-cell circulation and might be a factor contributing to the pathology of MS, chronic lymphocytic leukemia, and primary immunodeficiencies.
KW  - Sphingosine-1-phosphate
KW  - B cells
KW  - migration
KW  - autoimmunity
KW  - circulation
KW  - fingolimod
KW  - FTY720
KW  - primary immunodeficiencies
Y1  - 2014
U6  - https://doi.org/10.1016/j.jaci.2014.01.037
SN  - 0091-6749
SN  - 1097-6825
VL  - 134
IS  - 2
SP  - 420
EP  - +
PB  - Elsevier
CY  - New York
ER  - 
TY  - JOUR
A1  - Fayyaz, Susann
A1  - Henkel, Janin
A1  - Japtok, Lukasz
A1  - Krämer, Stephanie
A1  - Damm, Georg
A1  - Seehofer, Daniel
A1  - Püschel, Gerhard Paul
A1  - Kleuser, Burkhard
T1  - Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P(2) receptor subtype
JF  - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
N2  - Enhanced plasma levels of NEFA have been shown to induce hepatic insulin resistance, which contributes to the development of type 2 diabetes. Indeed, sphingolipids can be formed via a de novo pathway from the saturated fatty acid palmitate and the amino acid serine. Besides ceramides, sphingosine 1-phosphate (S1P) has been identified as a major bioactive lipid mediator. Therefore, our aim was to investigate the generation and function of S1P in hepatic insulin resistance.
 The incorporation of palmitate into sphingolipids was performed by rapid-resolution liquid chromatography-MS/MS in primary human and rat hepatocytes. The influence of S1P and the involvement of S1P receptors in hepatic insulin resistance was examined in human and rat hepatocytes, as well as in New Zealand obese (NZO) mice.
 Palmitate induced an impressive formation of extra- and intracellular S1P in rat and human hepatocytes. An elevation of hepatic S1P levels was observed in NZO mice fed a high-fat diet. Once generated, S1P was able, similarly to palmitate, to counteract insulin signalling. The inhibitory effect of S1P was abolished in the presence of the S1P(2) receptor antagonist JTE-013 both in vitro and in vivo. In agreement with this, the immunomodulator FTY720-phosphate, which binds to all S1P receptors except S1P(2), was not able to inhibit insulin signalling.
 These data indicate that palmitate is metabolised by hepatocytes to S1P, which acts via stimulation of the S1P(2) receptor to impair insulin signalling. In particular, S1P(2) inhibition could be considered as a novel therapeutic target for the treatment of insulin resistance.
KW  - FTY720
KW  - Insulin signalling
KW  - Palmitate
KW  - S1P receptors
KW  - Sphingolipids
KW  - Sphingosine 1-phosphate
Y1  - 2014
U6  - https://doi.org/10.1007/s00125-013-3123-6
SN  - 0012-186X
SN  - 1432-0428
VL  - 57
IS  - 2
SP  - 373
EP  - 382
PB  - Springer
CY  - New York
ER  -