sphingosine-1-phosphate and Lupus-Erythematosus--Systemic

Systemic lupus erythematosus is an autoimmune disease characterized by overproduction of type 1 IFN that causes multiple organ dysfunctions. Plasmacytoid dendritic cells (pDCs) that secrete large amounts of IFN have recently been implicated in the initiation of the disease in preclinical mouse models. Sphingosine-1-phosphate, a bioactive sphingolipid metabolite, is produced by 2 highly conserved isoenzymes, sphingosine kinase (SphK) 1 and SphK2, and regulates diverse processes important for immune responses and autoimmunity. However, not much is known about the role of SphK2 in autoimmune disorders. In this work, we examined the role of SphK2 in pDC development and activation and in the pristane-induced lupus model in mice that mimics the hallmarks of the human disease. Increases in pDC-specific markers were observed in peripheral blood of SphK2 knockout mice. In agreement, the absence of SphK2 increased the differentiation of FMS-like tyrosine kinase 3 ligand dendritic cells as well as expression of endosomal TLRs, TLR7 and TLR9, that modulate production of IFN. Surprisingly, however, SphK2 deficiency did not affect the initiation or progression of pristane-induced lupus. Moreover, although absence of SphK2 increased pDC frequency in pristane-induced lupus, there were no major changes in their activation status. Additionally, SphK2 expression was unaltered in lupus patients. Taken together, our results suggest that SphK2 may play a role in dendritic cell development. Yet, because its deletion had no effect on the clinical lupus parameters in this preclinical model, inhibitors of SphK2 might not be useful for treatment of this devastating disease.-Mohammed, S., Vineetha, N. S., James, S., Aparna, J. S., Lankadasari, M. B., Allegood, J. C., Li, Q.-Z., Spiegel, S., Harikumar, K. B. Examination of the role of sphingosine kinase 2 in a murine model of systemic lupus erythematosus.

Topics: Adolescent; Adult; Animals; Apoptosis; Ascitic Fluid; Gene Expression Regulation, Enzymologic; Humans; Lupus Erythematosus, Systemic; Lysophospholipids; Mice; Middle Aged; Peritoneal Lavage; Phosphotransferases (Alcohol Group Acceptor); Sphingosine; Terpenes; Young Adult

The failure of apoptotic cell clearance is linked to autoimmune diseases, nonresolving inflammation, and developmental abnormalities; however, pathways that regulate phagocytes for efficient apoptotic cell clearance remain poorly known. Apoptotic cells release find-me signals to recruit phagocytes to initiate their clearance. Here we found that find-me signal sphingosine 1-phosphate (S1P) activated macrophage erythropoietin (EPO) signaling promoted apoptotic cell clearance and immune tolerance. Dying cell-released S1P activated macrophage EPO signaling. Erythropoietin receptor (EPOR)-deficient macrophages exhibited impaired apoptotic cell phagocytosis. EPO enhanced apoptotic cell clearance through peroxisome proliferator activated receptor-γ (PPARγ). Moreover, macrophage-specific Epor(-/-) mice developed lupus-like symptoms, and interference in EPO signaling ameliorated the disease progression in lupus-like mice. Thus, we have identified a pathway that regulates macrophages to clear dying cells, uncovered the priming function of find-me signal S1P, and found a role of the erythropoiesis regulator EPO in apoptotic cell disposal, with implications for harnessing dying cell clearance.

Topics: Animals; Apoptosis; Cell Line; Erythropoietin; Female; Immune Tolerance; Lupus Erythematosus, Systemic; Lysophospholipids; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Paracrine Communication; Phagocytosis; PPAR gamma; Receptors, Erythropoietin; Signal Transduction; Sphingosine

CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase Cγ1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway could be an attractive therapeutic approach for SLE treatment.

Topics: Animals; Calcium Signaling; Cells, Cultured; Disease Models, Animal; fas Receptor; Female; Humans; Inflammation; Interferon-gamma; Interleukin-17; Lupus Erythematosus, Systemic; Lysophospholipids; Mice; Mice, Inbred MRL lpr; Peptide Fragments; Phospholipase C gamma; Protein Interaction Domains and Motifs; Sphingosine; T-Lymphocytes, Regulatory; Th17 Cells; Transcriptome; Transendothelial and Transepithelial Migration

Sphingosine-1-phosphate (S1P) is an active sphingolipid with chemotactic abilities and has been linked to inflammatory mediators and autoimmune disease. The aim of this study was to assess whether children with juvenile-onset systemic lupus erythematosus (JSLE) express increased systemic and/or urinary concentrations of S1P.. A subgroup of patients participating in the UK JSLE Cohort Study, were invited to participate. Cross sectional serum and urine samples were prospectively collected along with demographic and standard clinical data. Results were compared to a cohort of disease controls (Henoch Schonlein Purpura; HSP) and healthy controls (HC).. The median age of JSLE patients (n = 15) was 13.6 years (7.2-16.9 years). The serum concentrations of S1P in JSLE patients (7.4 uM, IQR 6.3-12.3 uM) were statistically significantly increased when compared to patients with HSP (n = 10; 5.2 uM, IQR 4.0-7.9 uM; p = 0.016) and HCs (n = 10; 3.8 uM, IQR 2.1-5.8 uM; p = 0.003). There was a trend towards increased serum S1P concentrations between patients with active lupus nephritis (n = 8; 8.7 uM, IQR 6.2-15.3 uM) compared to lupus non-nephritis (n = 7; 6.6 uM, IQR 6.3-10.6 uM; p = 0.355). No relationship was found between disease activity markers and S1P. Urine S1P concentrations were no different between JSLE patients (56.0 nM, IQR 40.3-96.6 nM) and HCs (58.7 nM, IQR 0-241.9 nM; p = 0.889).. We have demonstrated, for the first time, an increased serum concentration of S1P in a cohort of JSLE patients. These findings highlight a role of S1P in the pathophysiology of JSLE that warrants further investigation.

Topics: Adolescent; Child; Cohort Studies; Female; Humans; Lupus Erythematosus, Systemic; Lysophospholipids; Male; Sphingosine; United Kingdom