S1P d20:1, an endogenous modulator of S1P d18:1/S1P₂‐dependent signaling

Abstract

Sphingosine 1‐phosphate (S1P) signaling influences numerous cell biological mechanisms such as differentiation, proliferation, survival, migration, and angiogenesis. Intriguingly, our current knowledge is based solely on the role of S1P with an 18‐carbon long‐chain base length, S1P d18:1. Depending on the composition of the first and rate‐limiting enzyme of the sphingolipid de novo metabolism, the serine palmitoyltransferase, other chain lengths have been described in vivo. While cells are also able to produce S1P d20:1, its abundance and function remains elusive so far. Our experiments are highlighting the role of S1P d20:1 in the mouse central nervous system (CNS) and human glioblastoma. We show here that S1P d20:1 and its precursors are detectable in both healthy mouse CNS‐tissue and human glioblastoma. On the functional level, we focused our work on one particular, well‐characterized pathway, the induction of cyclooxygenase (COX)‐2 expression via the S1P receptor 2 (S1P2). Intriguingly, S1P d20:1 only fairly induces COX‐2 expression and can block the S1P d18:1‐induced COX‐2 expression mediated via S1P2 activation in the human glioblastoma cell line LN229. This data indicates that S1P d20:1 might act as an endogenous modulator of S1P signaling via a partial agonism at the S1P2 receptor. While our findings might stimulate further research on the relevance of long‐chain base lengths in sphingolipid signaling, the metabolism of S1P d20:1 has to be considered as an integral part of S1P signaling pathways in vivo.

Immunomodulatory sphingosine-1-phosphates as plasma biomarkers of Alzheimer’s disease and vascular cognitive impairment

“…First, the postulate that dysregulated S1P-mediated immunomodulation is involved in AD and VCI is necessarily an over-simplification, as the myriad S1P species as well as receptors and signaling partners indicate a much more complicated picture for S1P-mediated immunomodulation. A case in point is the recent study by Vutukuri et al [60] showing functional antagonism by d20:1 S1P on d18:1-mediated induction of cyclooxygenase (COX)-2 expression. As another example, we have not studied in detail the other two S1P species we measured (d17:1, d18:0) when they did not show significant alterations at the univariate analyses stage (see Table 2, Fig.…”

“…One important research gap is the elucidation of the specific S1P receptor subtypes mediating the immunomodulatory effects of d16:1 and d18:1 S1P. Previous work by others has suggested the potential involvement of S1PR 2 and S1PR 3 [42,60], while we have shown recently that d16:1 S1P has a lower potency for S1PR 2 and a lower efficacy for S1PR 3 [58]. Increasing d16:1 S1P concentrations would result in a reduction of pro-inflammatory S1PR 3 signaling, while having an additive effect on S1PR 1 and a minimal effect on S1PR 2 , thus indicating that the partial agonist effects of d16:1 S1P are receptor isoform-dependent.…”

A reference map of sphingolipids in murine tissues

“…Data indicate a distinct functional relevance of SP with C20-SPH, and their accumulation can cause compromised neural and retinal functions (Zhao et al, 2015). The function of S1P d20:1 was not clear until very recently, when it was shown to block the S1P d18:1-induced COX-2 expression mediated via S1P2 activation in the nervous system of murine models (Vutukuri et al, 2020). This discovery might suggest an important role as pathway modulator for the different existing forms of S1P also in other tissues.…”

Mitofusin 2 Deficiency Causes Pro-Inflammatory Effects in Human Primary Macrophages

“…Prostanoid analysis was carried out as previously described (31). Macrophages were cultured at 10 6 /well in 6-well plates.…”