sphingosine-1-phosphate and Crohn-Disease

Sphingosine-1-phosphate (S1P) belongs to the group of biologically active sphingolipids. Because of its ability to regulate the migration of lymphocytes, S1P constitutes an important element of pathophysiology of several diseases, such as: lupus erythematosus, multiple sclerosis or inflammatory bowel diseases. Inflammatory bowel diseases (IBD) are the group of chronic and recurrent diseases of the gastrointestinal tract. The most common among IBD are: Crohn’s disease and ulcerative colitis. Drugs that are currently used in the therapy of IBD alleviate symptoms, improve patients’ quality of life and induce remission but their efficacy is not satisfactory. Modulators of S1P receptors constitu­te an emerging option in the therapy of IBD. In this review we will discuss the role of S1P, its receptor and enzymes that participate in the metabolism of S1P under physiological conditions and in the course of IBD. Moreover, we will sum up the results of preclinical and clinical studies on S1P receptors modulators in IBD.. Sfingozyno-1-fosforan (S1P) jest przedstawicielem sfingolipidów o wysokiej aktywno-ści biologicznej. Ze względu na swój wpływ na migrację komórek odpornościowych uznawany jest za istotny element w patogenezie wielu chorób, takich jak: toczeń układowy, stwardnienie rozsiane czy nieswoiste choroby zapalne jelit (NChZJ). Nieswoiste choroby zapalne jelit to grupa przewlekłych i postępujących schorzeń układu pokarmowego, które przebiegają z okresami zaostrzeń i remisji. Do najczęstszych zalicza się: chorobę Leśniow-skiego-Crohna (ChLC) oraz wrzodziejące zapalenie jelita grubego (WZJG). Obecnie w le-czeniu NChZJ stosuje się związki o działaniu przeciwzapalnym i immunomodulującym, których zadaniem jest złagodzenie objawów oraz wprowadzenie pacjenta w stan remisji. W ramach tego artykułu omówiona zostanie rola S1P, receptora dla S1P oraz enzymów bio-rących udział w jego metabolizmie w warunkach fizjologicznych oraz w przebiegu NChZJ. Ponadto, podsumowane zostaną wyniki badań przedklinicznych i klinicznych nad skutecz-nością modulatorów receptora dla S1P w przebiegu NChZJ.

Topics: Colitis, Ulcerative; Crohn Disease; Humans; Inflammatory Bowel Diseases; Lysophospholipids; Quality of Life; Sphingosine

Lymphocytes recirculate from tissues to blood following the sphingosine-1-phosphate (S1P) gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, among which the S1P lyase (SPL) irreversibly degrades S1P. The role of SPL in the intestine, both during homeostasis and IBD, is poorly understood. We hypothesized that modulation of tissue S1P levels might be advantageous over S1P receptor (S1PR) agonists (eg, fingolimod, ozanimod, etrasimod), as without S1PR engagement there might be less likelihood of potential off-target effects.. First we examined SPL mRNA transcripts and SPL localization in tissues by quantitative reverse transcription polymerase chain reaction and immunohistochemistry. The in vivo effects of the SPL inhibitors 4-deoxypyridoxine hydrochloride (30 mg/L) and 2-acetyl-4 (tetrahydroxybutyl)imidazole (50 mg/L) were assessed through their oral administration to adult TNF∆ARE mice, which spontaneously develop Crohn's-like chronic ileitis. The effect of SPL inhibition on circulating and tissue lymphocytes, transcriptional regulation of proinflammatory cytokines, and on the histological severity of ileitis was additionally examined. Tissue S1P levels were determined by liquid chromatography-mass spectrometry. Mechanistically, the potential effects of high S1P tissue levels on intestinal leukocyte apoptosis were assessed via terminal deoxynucleotidyl transferase dUTP nick end-labeling assay and annexin 5 staining. Finally, we examined the ability of T cells to home to the intestine, along with the effects of SPL inhibition on cellular subsets within immune compartments via flow and mass cytometry.. S1P lyase was ubiquitously expressed. In the gut, immunohistochemistry predominantly localized it to small intestinal epithelia, although the lamina propria leukocyte fraction had higher mRNA transcripts. Inhibition of SPL markedly increased local intestinal S1P levels, induced peripheral lymphopenia, downregulated proinflammatory cytokines, and attenuated chronic ileitis in mice. SPL inhibition reduced T and myeloid cells in secondary lymphoid tissues and the intestine and decreased naïve T-cell recruitment. The anti-inflammatory activity of SPL inhibition was not mediated by leukocyte apoptosis, nor by interference with the homing of lymphocytes to the intestine, and was independent of its peripheral lymphopenic effect. However, SPL inhibition promoted thymic atrophy and depleted late immature T cells (CD4+CD8+ double positive), with accumulation of mature CD4+CD8- and CD4-CD8+ single-positive cells.. Inhibition of the S1P lyase alters the S1P gradient and attenuates chronic ileitis via central immunosuppression. SPL inhibition could represent a potential way to tame an overactive immune response during IBD and other T-cell-mediated chronic inflammatory diseases.

Topics: Aldehyde-Lyases; Animals; Anti-Inflammatory Agents; Crohn Disease; Ileitis; Lysophospholipids; Mice; Sphingosine; Thymocytes; Tumor Necrosis Factor-alpha