sphingosine-1-phosphate and Arthritis

Conventional and biologic disease-modifying antirheumatic drugs have revolutionized the medical therapy of inflammatory arthritis. However, it remains unclear as to what can be done to treat immune-mediated chronic inflammation after patients become refractory to these therapies or develop serious side-effects and/or infections forcing drug withdrawal. Because of these concerns it is imperative that novel targets be continuously identified and experimental strategies designed to test potential arthritis interventions in vitro, but more importantly, in well-validated animal models of inflammatory arthritis. Over the past few years, sphingosine-1-phosphate, interleukin-7 receptor, spleen tyrosine kinase, extracellular signal-regulated kinase, mitogen-activated protein kinase 5/p38 kinase regulated/activated protein kinase, micro-RNAs, tumor necrosis factor-related apoptosis inducing ligand and the polyubiquitin-proteasome pathway were identified as promising novel targets for potential antiarthritis drug development. Indeed several experimental compounds alter the biological activity of these targets and have shown clinical efficacy in animal models of arthritis. A few of them have even entered the first phase of human clinical trials.

Topics: Animals; Antirheumatic Agents; Arthritis; Drug Discovery; Humans; Inflammation; Inflammation Mediators; Intracellular Signaling Peptides and Proteins; Lysophospholipids; MicroRNAs; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Proteasome Inhibitors; Protein-Tyrosine Kinases; Receptors, Interleukin-7; Receptors, TNF-Related Apoptosis-Inducing Ligand; Sphingosine; Syk Kinase

Lymphatic endothelial cells (LECs) present peripheral tissue antigens to induce T cell tolerance. In addition, LECs are the main source of sphingosine-1-phosphate (S1P), promoting naive T cell survival and effector T cell exit from lymph nodes (LNs). Autophagy is a physiological process essential for cellular homeostasis. We investigated whether autophagy in LECs modulates T cell activation in experimental arthritis. Whereas genetic abrogation of autophagy in LECs does not alter immune homeostasis, it induces alterations of the regulatory T cell (T reg cell) population in LNs from arthritic mice, which might be linked to MHCII-mediated antigen presentation by LECs. Furthermore, inflammation-induced autophagy in LECs promotes the degradation of Sphingosine kinase 1 (SphK1), resulting in decreased S1P production. Consequently, in arthritic mice lacking autophagy in LECs, pathogenic Th17 cell migration toward LEC-derived S1P gradients and egress from LNs are enhanced, as well as infiltration of inflamed joints, resulting in exacerbated arthritis. Our results highlight the autophagy pathway as an important regulator of LEC immunomodulatory functions in inflammatory conditions.

Topics: Animals; Arthritis; Autoimmunity; Cell Movement; Cells, Cultured; Endothelial Cells; Humans; Immune Tolerance; Inflammation; Lymph Nodes; Lymphatic Vessels; Lysophospholipids; Macroautophagy; Mice; Mice, Inbred C57BL; Sphingosine; T-Lymphocytes, Regulatory; Th17 Cells

T-helper (Th) lymphocytes contribute to arthritis pathogenesis by helping B cells to produce antibodies, by producing cytokines that activate effector cells involved in the destruction of cartilage and bone, and by contributing to osteoclast differentiation. There are murine models of arthritis, most notably collagen- and proteoglycan-induced arthritis, in which arthritis depends on T-cell recognition of antigens that are expressed in the joints. In spite of this, we still do not know the antigens recognised by arthritogenic Th cells in humans. Moreover, current evidence for Th cells exerting arthritogenic effector functions within the joints is only indirect.

Topics: Animals; Antigens; Arthritis; Arthritis, Experimental; Disease Models, Animal; Fingolimod Hydrochloride; Humans; Joints; Lysophospholipids; Mice; Propylene Glycols; Sphingosine; T-Lymphocytes, Helper-Inducer

Sphingosine kinase 1 (SphK1) is an enzyme that converts sphingosine to bioactive sphingosine-1-phosphate. Recent in vitro data suggest a potential role of SphK1 in TNF-alpha-mediated inflammation. Our aims in this study were to determine the in vivo significance of SphK1 in TNF-alpha-mediated chronic inflammation and to define which pathogenic mechanisms induced by TNF-alpha are SphK1 dependent. To pursue these aims, we studied the effect of SphK1 deficiency in an in vivo model of TNF-alpha-induced chronic inflammatory arthritis. Transgenic hTNF-alpha mice, which develop spontaneous inflammatory erosive arthritis beginning at 14-16 wk, were crossed with SphK1 null mice (SphK1(-/-)), on the C57BL6 genetic background. Beginning at 4 mo of age, hTNF/SphK1(-/-) mice had significantly less severe clinically evident paw swelling and deformity, less synovial and periarticular inflammation, and markedly decreased bone erosions as measured quantitatively through micro-CT images. Mechanistically, the mice lacking SphK1 had less articular cyclooxygenase 2 protein and fewer synovial Th17 cells than did hTNF/SphK1(+/+) littermates. Microarray analysis and real-time RT-PCR of the ankle synovial tissue demonstrated that hTNF/SphK1(-/-) mice had increased transcript levels of suppressor of cytokine signaling 3 compared with hTNF/SphK1(+/+) mice, likely also contributing to the decreased inflammation in the SphK1-deficient mice. Finally, significantly fewer mature osteoclasts were detected in the ankle joints of hTNF/SphK1(-/-) mice compared with hTNF/SphK1(+/+) mice. These data indicate that SphK1 plays a key role in hTNF-alpha-induced inflammatory arthritis via impacting synovial inflammation and osteoclast number.

Topics: Animals; Ankle Joint; Arthritis; Cyclooxygenase 2; Female; Foot Joints; Gene Expression Profiling; Humans; Immunoblotting; Immunohistochemistry; Joints; Lysophospholipids; Male; Mice; Mice, Knockout; Mice, Transgenic; Osteoclasts; Phosphotransferases (Alcohol Group Acceptor); Reverse Transcriptase Polymerase Chain Reaction; Severity of Illness Index; Sphingolipids; Sphingosine; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Synovial Membrane; Synovitis; Tumor Necrosis Factor-alpha