Highlights
- •Sphingosine-1-phosphate (S1P) receptor 1 subtype (S1PR1) mechanisms in the spinal cord producing mechanohypersensitivity are unknown.
- •S1PR1 activation causes mechanohypersensitivity via NLRP3 neuroinflammation.
- •The inhibition of S1PR1-mediated mechanohypersensitivity is dependent on IL-10.
- •Astrocytes are a cellular substrate for S1PR1 activity.
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 spinal cord contributes to the development of nociception while identifying
the cellular substrate for these activities.
Perspective
This study is the first to link the activation of NLRP3 and IL-1β signaling in the
spinal cord and S1PR1 signaling in astrocytes to the development of S1PR1-evoked mechanoallodynia.
These findings provide critical basic science insights to support the development
of therapies targeted toward S1PR1.
Key words
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Article info
Publication history
Published online: February 22, 2019
Accepted:
February 16,
2019
Received in revised form:
January 29,
2019
Received:
September 13,
2018
Footnotes
Funded by the American Pain Society Future Leaders in Pain Grant (APS15369; TMD), NIH T32 Training Grant GM008306 (KB and CMH) and Leukemia and Lymphoma Society grant (6241-13; DS. DS is the inventor of U.S. patents related to S1PR1, which are assigned to and owned by Saint Louis University. All other authors declare no competing financial interests.
Supplementary data accompanying this article are available online at www.jpain.org and www.sciencedirect.com.
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© 2019 by the American Pain Society
