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S1P Regulates the Recirculation of Tissue-Resident ILC2
Characterizing inhibitors of the S1P transporter, spinster homologue 2 (Spns2)
Tao Huang1, Yugesh Kharel1, Ariel Burgio2, Russell Fritzemeier2, Kyle Dunavant2, Christopher Shrader2, Webster L Santos2, Kevin R Lynch1
1Department of Pharmacology, University of Virginia, Charlottesville, VA
2Department of Chemistry and Center for Drug Discover, Virginia Tech, Blacksburg, VA
Abstract
Spns2 facilitates the movement of S1P from its intracellular site of synthesis to extracellular chaperones (HDL-bound ApoM, albumin) and thereby initiates the cascade of signaling via cell surface S1P receptors. The positioning of Spns2 just “upstream” of S1P receptors in the signaling cascade has led us and others to hypothesize that Spns2 inhibitors will recapitulate the efficacy of S1P receptor modulators without their adverse events, e.g., bradycardia. While the results of our studies with mice and rats support this hypothesis, we have found that Spns2 inhibitors are also anti-fibrotic in models of kidney fibrosis. The latter effect is not observed with S1P receptor modulators but rather is a property of sphingosine kinase type 2 inhibitors. Thus, Spns2, which lies between S1P synthesis and S1P receptors, might be a drug target for both autoimmune and fibrotic diseases. The mechanism of action of Spns2 remains uncertain. The expected (from genetically modified mouse studies) reduction in peripheral blood lymphocytes is observed soon after acute dosing of an Spns2 inhibitor and tracks with blood drug levels, but the predicted decrease in lymph [S1P] is observed only after chronic dosing. Further, the decrease in plasma [S1P], which is predicted by some, but not other, genetically modified mouse studies, is not consistently observed with Spns2 inhibitors.