Modulation of Spinghosine-1-Phosphate (S1P)/ S1P-Receptor Axis and Lymphocyte Function

Among the lipids that concentrate in lipid rafts, sphingolipids represent a major class that is metabolized to generate ceramide and subsequently sphingosine that in turn could be phosphorylated by sphingosine kinase (SPHK) (expressed mainly in platelets and in other peripheral blood cells) to generate S1P (Scanu and Edelstein 2008). Free or albumin-bound S1P is more susceptible to degradation than S1P bound to HDL (Yatomi 2008), which suggests that the latter might have a role in determining the uptake, cellular degradation, and systemic function. S1P carried by HDL positively correlates with HDL cholesterol, apoA-I, and apoA-II levels; furthermore, S1P is enriched in small dense HDL3 (Scanu and Edelstein 2008). S1P signals through five known G protein-coupled receptors (S1P1–S1P5). Over the last few years, it become apparent that S1P and the key enzymes SPHKs play a central role in the pathogenesis of several inflammatory disorders, including rheumatoid arthritis, asthma, and atherosclerosis by modulating macrophage function through the control of apoptosis as well as cell trafficking (Weigert et al. 2009). Many of these effects might depend on the activation of different S1P receptors. The activation of the lysosphingolipid receptor-PI3K/Akt axis by sphingosine-1phosphate or other S1P mimetics is responsible for the induction by HDL of several genes involved in the immune response including the long pentraxin PTX3 or the transforming growth factor beta 2 (Norata et al. 2005, 2008). The S1P/S1P-receptor axis also plays a key role in lymphocyte function. The activation of S1P receptors and the consequent downstream signaling facilitate the egress of T cells from lymphoid organs (Mandala et al. 2002; Matloubian et al. 2004) and play a role in the lineage determination of peripheral T cells (Liu et al. 2010). S1P inhibits the differentiation of forkhead box P3 (FoxP3)+ regulatory T cells (Tregs) while promoting the development of T helper type 1 (Th1) in a reciprocal manner (Liu et al. 2010). S1P receptor antagonizes TGF-β receptor function through an inhibitory effect on SMAD-3 activities to control the dichotomy between these two T-cell lineages (Liu et al. 2010). In animal models, apoA-I reduces inflammation in LDL receptor (-/-), apoA-I(-/-) mice by augmenting the effectiveness of the lymph nodes' Treg response, with an increase in Treg and a decrease in the percentage of effector/effector memory T cells (Wilhelm et al. 2010). While marked changes of Treg number/function (twoto threefold difference) have been associated with atheroprotective functions in animal models (Ait-Oufella et al. 2006; Mor et al. 2007), in humans the correlation between Treg, immune, and cardiometabolic disorders is less clear. We found no association between circulating CD3 + CD4 + CD25highCD127low Treg levels and the extent or progression of human atherosclerotic disease at carotid and coronary sites (Ammirati et al. 2010). In a series of immune-mediated diseases such as rheumatoid arthritis, increased Treg levels in synovial fluid of inflamed joints were observed (Mottonen et al. 2005; Bacchetta et al. 2007). Furthermore, Liu et al. observed relatively high Treg-cell levels in patients with type 1 diabetes mellitus (Liu et al. 2006), and pathogenic T cells have been shown to have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs (Grinberg-Bleyer et al. 2010). Of note, excessive IL-6 or TNF-alpha production was associated with increased Treg levels (Fujimoto et al. 2011; Bilate and Lafaille 2010). This evidence suggests the possibility that Treg numbers could increase during some stages of disease as an attempt to regulate effector-cell activity. Unexpectedly, in the general population, we observed an inverse relation between HDL-C and Treg count (Ammirati et al. 2010); whether this finding suggests that HDL could influence the polarization of lymphocyte subsets or could be a bystander of the T-cell status remains to be addressed. Recent evidence on the role of S1P in immune surveillance and the discovery of regulatory mechanisms in S1P-mediated immune trafficking has prompted extensive investigation in the field of S1P-receptor pharmacology. Fingolimod (FTY720), an S1P-receptor modulator, prevents lymphocyte egress from lymph nodes and modulates lymphocyte differentiation (Chi 2011). Initially, fingolimod was used as immunosuppressant in solid organ transplantation (Tedesco-Silva et al. 2006), while MS has been the first disease in which fingolimod was tested. In MS the myelin sheaths around the axons of the brain and spinal cord are damaged by inflammatory processes, leading to demyelination. Current therapeutic approaches are focused on the suppression of the immune system and on the blockage of T-cell blood–brain barrier transmigration into the brain parenchyma. Treatment with fingolimod was effective in reducing the disability progression on a large cohort of patients with relapsing MS (Cohen et al. 2010; Kappos et al. 2010). Of note, MS patients during the phase of clinical remission showed increased levels of HDL and total cholesterol levels (Salemi et al. 2010), whereas in immune-mediated disorders with increased markers of systemic inflammation, HDL levels are often decreased. Fingolimod was assessed also in diseases with an immunological component, such as atherosclerosis (Nofer et al. 2007; Keul et al. 2007). In LDL receptor-deficient mice, fingolimod inhibits atherosclerosis by modulating lymphocyte and macrophage function. In this study plasma lipids remained unchanged during the course of fingolimod treatment, whereas fingolimod lowered blood lymphocyte count (Nofer et al. 2007). As S1P levels are increased in many inflammatory conditions, such as in asthma and autoimmunity, the exact mechanism by which S1PR agonists could modulate its function is debated (Rivera et al. 2008). Interestingly, fingolimod is highly active in inducing the internalization, ubiquitination, and subsequent degradation of S1PR1 (Graler and Goetzl 2004) which suggests that its inhibitory action on immune cell trafficking might be through receptor downregulation. It is therefore crucial to understand the effect of HDL contained S1P on receptor expression and activity in immune disorders.

In spite of the presence of a number of experimental and clinical observations suggesting a relation between HDL and innate immunity, several questions remain to be addressed. Are the altered HDL-C levels a consequence of the atherogenic process, a cause of increased atherosclerosis observed in immune disorders, or independently related to the latter? How is HDL function altered in these diseases? Does raising HDL-C improve the outcome of immune disorders? As HDLs are a reservoir for several biologically active substances that may impact the immune system (Norata et al. 2012), how does the fine-tuning of lipid and protein exchange among lipoproteins affect HDL-related immune functions? Is there a specific HDL subfraction that is relevant? Addressing these aspects will be critical to understand the connection between HDL and the immune response.

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