Activation of Sphingosine-1-Phosphate Receptor 1 in the Spinal Cord Produces Mechanohypersensitivity Through the Activation of Inflammasome and IL-1β Pathway

The Journal of Pain : Official Journal of the American Pain Society
Timothy DoyleDaniela Salvemini

Abstract

Sphingosine-1-phosphate (S1P) receptor 1 subtype (S1PR1) activation by its ligand S1P in the dorsal horn of the spinal cord causes mechanohypersensitivity. The cellular and molecular pathways remain poorly understood. We report that the activation of S1PR1 with an intrathecal injection of the highly selective S1PR1 agonist SEW2871 led to the development of mechanoallodynia by activating the nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome (increased expression of NLRP3, cleaved caspase 1 and mature IL-1β) in the dorsal horn of the spinal cord. The functional S1PR1 antagonist FTY720 blocked NLRP3 activation and IL-1β production. Moreover, inhibiting IL-10 signaling with an intrathecal injection of an anti-IL-10 antibody attenuated the beneficial effects exerted by FTY720. This finding suggests that disrupting S1PR1 signaling engages beneficial IL-10-dependent pathways. Notably, we found that mice with astrocyte-specific deletions of S1pr1 did not develop mechanoallodynia after intrathecal injection of SEW2871 and exhibited decreased levels of cleaved caspase 1, identifying astrocytes as a key cellular locus for S1PR1 activity. Our findings provide novel mechanistic insights on how S1PR1 activation in the ...Continue Reading

Citations

Jun 27, 2020·Expert Opinion on Therapeutic Targets·Michiel Langeslag, Michaela Kress
Oct 2, 2019·Frontiers in Molecular Neuroscience·Geoffroy LaumetAnnemieke Kavelaars
Jun 18, 2020·International Journal of Molecular Sciences·Kim M A De Kleijn, Gerard J M Martens
May 10, 2019·Proceedings of the National Academy of Sciences of the United States of America·Zhoumou ChenDaniela Salvemini
May 25, 2021·The Journal of Pain : Official Journal of the American Pain Society·Jennifer S LabusAndrea Rapkin
Nov 14, 2021·Cellular and Molecular Neurobiology·Filomena LauroDaniela Salvemini

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