Postnatal deletion of Spns2 prevents neuroinflammation without compromising blood vascular functions

Hasan, Zafrul; Nguyen, Thang; Lam, Brenda Wan Shing; Wong, Jovi Hui Xin; Wong, Caleb; Tan, Clarissa; Yu, Jiabo; Thiam, Chung Hwee; Zhang, Yongliang; Angeli, Véronique; Nguyen, Long N.

doi:10.1007/s00018-022-04573-y

Cited by 5 publications

(12 citation statements)

References 47 publications

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“…Further, 33p was found to exert this effect at 16 h post administration in a dose-dependent manner (Figure B). These results are consistent with the phenotype that is observed with Spns2-knockout mice suggesting in vivo target engagement. , However, neither 32p nor 33p administration resulted in a significant decrease in plasma [S1P] (Figure C), which is unlike our experience with our first-generation Spns2 inhibitor, SLF1081851 . As mentioned previously, the literature regarding genetically modified, Spns2-deficient mice is contradictory on this point.…”

Section: Resultssupporting

confidence: 89%

“…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: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

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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“…Spns2 null mice 15,16 and endothelium-specific 17,18 Spns2-deficient mice have significantly reduced (~50%) peripheral blood lymphocyte counts compared to control mice, which is reminiscent of the response to SRM administration. Spns2 null mice also have negligible S1P in thoracic duct lymph compared to control mice 17,18,19 . Together, these facts suggest that STBs (S1P transport blockers, specifically, Spns2-dependent S1P transport) and SRMs have similar mechanisms of action.…”

Section: Introductionmentioning

confidence: 94%

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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“…In search for a potential lysosomal transporter of sphingosines, we identified Spinster protein homolog 1 (SPNS1), which belongs to a small family of 3 mammalian proteins, namely SPNS1-3. Human SPNS1 shares 57% identities with human SPNS2, which is a plasma membrane transporter for sphingosine-1-phosphate (S1P) (8)(9)(10). Additionally, several studies have shown that SPNS1 is expressed in the lysosomes and plays a role in the autophagic pathway (11).…”

Section: Introductionmentioning

confidence: 99%

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

Nguyen

et al. 2022

Preprint

Self Cite

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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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Postnatal deletion of Spns2 prevents neuroinflammation without compromising blood vascular functions

Cited by 5 publications

References 47 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)

Assessing Spns2-dependent S1P Transport as a Prospective Therapeutic Target

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

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