Mfsd2b and Spns2 are essential for maintenance of blood vessels during development and in anaphylactic shock

Le, Thanh Nha Uyen; Nguyen, Quoc Toan; Kalailingam, Pazhanichamy; Yen, Nguyen Thi Hai; Sukumar, Viresh Krishnan; Tan, Clarissa; Tukijan, Farhana; Couty, Ludovic; Hasan, Zafrul; Gaudio, Ilaria Del; Wenk, Markus R.; Cazenave-Gassiot, Amaury; Camerer, Eric; Nguyen, Long N.

doi:10.1016/j.celrep.2022.111208

Cited by 9 publications

(7 citation statements)

References 57 publications

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“…As mentioned previously, the literature regarding genetically modified, Spns2-deficient mice is contradictory on this point. Specifically, mice rendered deficient in Spns2 by genetic manipulation of its gene are variously reported to have no significant change, ,, an ∼23% decrease, a 25–30% decrease, a 40% decrease, and a 45% decrease in plasma S1P concentrations. We do not understand what underlies these discrepancies and why our early Spns2 inhibitor, SLF1081851 , consistently reduced plasma S1P concentrations by ∼20%, while our subsequent inhibitors evoke no significant changes in mice, and we know of no other manipulation of the S1P pathway that changes plasma S1P concentrations without changing red blood cell S1P concentrations.…”

Section: Resultsmentioning

confidence: 99%

“…Spns2, which is expressed by the endothelium, is expected to be both the source of lymph S1P and some fraction of plasma S1P. While studies using Spns2 -knockout mice invariably report that Spns2-deficient mice have significantly diminished blood lymphocyte counts, the same literature is contradictory regarding both plasma and lymph [S1P] in these animals. ,− In the standard model of multiple sclerosis (EAE, Experimental Autoimmune Encephalomyelitis), germ line deletion of Spns2 in mice resulted in improvement of clinical scores . In addition, Spns2 “knockdown” in human renal cell lines showed decreased expression of pro-fibrotic cytokines including fibronectin and connective tissue growth factor, suggesting Spns2 could have therapeutic benefits for renal fibrosis .…”

Section: Introductionmentioning

confidence: 99%

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2-Aminobenzoxazole Derivatives as Potent Inhibitors of the Sphingosine-1-Phosphate Transporter Spinster Homolog 2 (Spns2)

et al. 2023

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The S1P1 receptor is the target of four marketed drugs for the treatment of multiple sclerosis and ulcerative colitis. Targeting an S1P exporter, specifically Spns2, that is “upstream” of S1P receptor engagement is an alternate strategy that might recapitulate the efficacy of S1P receptor modulators without cardiac toxicity. We recently reported the first Spns2 inhibitor SLF1081851 (16d) that has modest potency with in vivo activity. To develop more potent compounds, we initiated a structure–activity relationship study that identified 2-aminobenzoxazole as a viable scaffold. Our studies revealed SLB1122168 (33p), which is a potent inhibitor (IC50 = 94 ± 6 nM) of Spns2-mediated S1P release. Administration of 33p to mice and rats resulted in a dose-dependent decrease in circulating lymphocytes, a pharmacodynamic indication of Spns2 inhibition. 33p provides a valuable tool compound to explore both the therapeutic potential of targeting Spns2 and the physiologic consequences of selective S1P export inhibition.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

2-Aminobenzoxazole Derivatives as Potent Inhibitors of the Sphingosine-1-Phosphate Transporter Spinster Homolog 2 (Spns2)

et al. 2023

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“…In search for a lysosomal protein with potential transport functions for sphingosines from lysosomes, we identified SPNS1 as a candidate. SPNS1 shares a high sequence identity with SPNS2, a sphingosine-1-phosphate (S1P) transporter from endothelial cells (14), (15), (16). SPNS1 protein is detected in the lysosomal protein fractions (11).…”

Section: Resultsmentioning

confidence: 99%

SPNS1 is required for the transport of lysosphingolipids and lysoglycerophospholipids from lysosomes

Nguyen

et al. 2022

Preprint

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Accumulation of sphingolipids, especially sphingosines, in the lysosomes is attributed to the pathogenesis of several lysosomal storage diseases. In search for a lysosomal protein that mediates the release of sphingosines, we identified SPNS1 which shares the highest homology to SPNS2, a sphingosine-1-phosphate (S1P) transporter. We generated knockout cells and mice for Spns1 and employed lipidomics and metabolomics to identify SPNS1 ligands. We found that knockouts of Spns1 resulted in the accumulation of sphingolipids, including sphingosines in embryonic brains and cell lines. These results suggest that deficiency of SPNS1 affects the clearance of sphingolipids in lysosomes. Biochemical assays demonstrated that sphingosines released from lysosomes required SPNS1. Furthermore, by performing a comprehensive analysis of metabolites from livers of postnatal Spns1 knockout mice (gSpns1-cKO), we detected a striking accumulation of lysoglycerophospholipids including LPC, LPE, LPG, and lysoplasmalogens. Interestingly, the release of these lysoglycerophospholipids also required SPNS1. Global knockout of Spns1 (gSpns1-KO) resulted in embryonic lethality between E12.5-E13.5 with developmental defects. Postnatal deletion of Spns1 in mice caused lipid accumulation in the lysosomes and pathological conditions reminiscent of lysosomal storage diseases. These results reveal a critical molecular role of SPNS1 as a transporter for lysosphingolipids and lysoglyerophospholipids from the lysosomes and link its physiological functions with lysosomal storage diseases.

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“…Further, lymph S1P concentration, which was measured in some mouse strains, is nearly undetectable in the Spns2 deficient mice [17][18][19] . While the lymphopenia is consistently observed across multiple genetically manipulated mouse strains, the effect of Spns2 deficiency on plasma S1P concentrations is variously reported to be either not changed significantly 15,19,34 or decreased by up to 45% 16,17,35 . To this compendium, we add data obtained with our independently derived Spns2 -/mouse strain, which was generated on a mixed B6-SJL strain background using Crispr/Cas9 technology.…”

Section: Pharmacodynamics Of Stb Administrationmentioning

confidence: 99%

Assessing Spns2-dependent S1P Transport as a Prospective Therapeutic Target

Kharel,

Huang,

Dunnavant

et al. 2024

Preprint

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S1P (sphingosine 1-phosphate) receptor modulator (SRM) drugs interfere with lymphocyte trafficking by downregulating lymphocyte S1P receptors. While the immunosuppressive activity of SRM drugs has proved useful in treating autoimmune diseases such as multiple sclerosis, that drug class is beset by on-target liabilities such as initial dose bradycardia. The S1P that binds to cell surface lymphocyte S1P receptors is provided by S1P transporters. Mice born deficient in one of these, spinster homolog 2 (Spns2), are lymphocytopenic and have low lymph S1P concentrations. Such observations suggest that inhibition of Spns2-mediated S1P transport might provide another therapeutically beneficial method to modulate immune cell positioning. We report here results using a novel S1P transport blocker (STB), SLF80821178, to investigate the consequences of S1P transport inhibition in rodents. We found that SLF80821178 is efficacious in a multiple sclerosis model but – unlike the SRM fingolimod – neither decreases heart rate nor compromises lung endothelial barrier function. Notably, although Spns2 null mice have a sensorineural hearing defect, mice chronically treated with SLF80821178 have normal hearing acuity. STBs such as SLF80821178 evoke a dose-dependent decrease in peripheral blood lymphocyte counts, which provides a reliable pharmacodynamic marker of target engagement. However, the maximal reduction in circulating lymphocyte counts in response to SLF80821178 is substantially less than the response to SRMs such as fingolimod (50% vs. 90%) due to a lesser effect on T lymphocyte sub-populations by SLF80821178. Finally, in contrast to results obtained with Spns2 deficient mice, lymph S1P concentrations were not significantly changed in response to administration of STBs at doses that evoke maximal lymphopenia, which indicates that current understanding of the mechanism of action of S1P transport inhibitors is incomplete.

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Mfsd2b and Spns2 are essential for maintenance of blood vessels during development and in anaphylactic shock

Cited by 9 publications

References 57 publications

2-Aminobenzoxazole Derivatives as Potent Inhibitors of the Sphingosine-1-Phosphate Transporter Spinster Homolog 2 (Spns2)

2-Aminobenzoxazole Derivatives as Potent Inhibitors of the Sphingosine-1-Phosphate Transporter Spinster Homolog 2 (Spns2)

SPNS1 is required for the transport of lysosphingolipids and lysoglycerophospholipids from lysosomes

Assessing Spns2-dependent S1P Transport as a Prospective Therapeutic Target

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