The confidential enquiry into maternal and child health (CEMACH)

TLDR

Sphingosine 1‑phosphate and its five high‑affinity receptors regulate immune, central nervous, and cardiovascular physiology, and down‑modulation of S1P1 blocks B and T‑cell egress from lymph nodes, a mechanism relevant to autoimmune diseases such as multiple sclerosis where autoreactive lymphocytes cause demyelination and brain atrophy. This review examines how S1P and S1PR signaling modulate normal physiology and how S1PR‑directed therapies, particularly fingolimod, can retain autoreactive lymphocytes in lymph nodes to prevent CNS infiltration and disease progression in multiple sclerosis. Fingolimod, a sphingosine analog, is phosphorylated in vivo to fingolimod phosphate by sphingosine kinase‑2, which binds S1PRs—especially S1P1—to sequester autoreactive lymphocytes in lymph nodes. Clinical studies show fingolimod phosphate reduces immune cell infiltration into the CNS of MS patients, while preclinical data indicate additional neuroprotective effects independent of immune trafficking.

Abstract

Sphingosine 1-phosphate (S1P) and 5 specific high-affinity S1P receptor (S1PR) subtypes, S1P_1–5, have important regulatory functions in normal physiology and disease processes, particularly involving the immune, central nervous, and cardiovascular systems. Within the immune system, downmodulation of S1P₁ prevents the egress of B and T cells from lymph nodes (LN) into the lymphatic circulation. This is especially relevant in certain autoimmune diseases, including multiple sclerosis (MS), in which demyelination and brain atrophy occur due to the presence of autoreactive lymphocytes within the CNS. Accordingly, S1P₁-directed pharmacologic interventions that aim to retain these autoreactive lymphocytes in the LN and thus prevent their recirculation and subsequent infiltration into the CNS have been investigated as a means of preventing disease progression in patients with MS. Fingolimod (FTY720), a structural analog of sphingosine, is phosphorylated in vivo into fingolimod phosphate by sphingosine kinase-2. Fingolimod phosphate, which binds to S1PRs, has been shown to modulate the activity of S1P₁ in patients with MS and to reduce immune cell infiltration into the CNS, consistent with its previously established effects in animal models of the disease. Preclinical studies also suggest that fingolimod has beneficial effects within the CNS that are independent of its immune cell trafficking activity. This review highlights the normal physiologic processes modulated by S1P and S1PRs, and the therapeutic effects of S1PR modulation in the immune, central nervous, and cardiovascular systems.