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Preprint WatchModerateAugust 29th, 2026

Sphingosine 1-phosphate receptor-1 signaling enhances neutrophil survival while suppressing inflammation and bacterial host defense functions

Lin, Y.-c.; Seno, T.; Hsu, A. Y.; Cartier, A.; Kuo, A.; Levesque, M. V.; Ghosh, A.; Fohmann, I.; Blaho, V. A.; Galvani, S.; Crocker, R.; Kazer, S. W.; Ordovas-Montanes, J.; Luo, H. R.; Hla, T.

S1PR1 signalling in neutrophils is claimed to promote mitochondrial fitness, enhance survival and reduce inflammatory output, redistributing neutrophils from bone marrow to peripheral tissues without overt inflammation, while impairing bacterial clearance in the lung and reducing lung injury during influenza A infection.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint assigns S1PR1 a neutrophil-intrinsic role that cuts against the trafficking-centred rationale behind S1P receptor modulators in inflammatory bowel disease. Claidex holds one S1PR1 post-mortem, etrasimod-s1pr1-crohns-cultivate-phase2-3-efficacy-failure, an efficacy failure in Crohn's disease. The clinical hypothesis for that class is lymphocyte sequestration in lymph nodes, so a receptor that also enhances neutrophil survival and suppresses neutrophil inflammatory output changes what antagonism is expected to do. If S1PR1 signalling dampens neutrophil inflammation, blocking it could release the very effector population the therapy is meant to quiet, which would blunt net benefit in a neutrophil-rich mucosal lesion. The infection findings sharpen the point: S1PR1 signalling impaired bacterial clearance in the lung but reduced influenza-driven lung injury, so the direction of effect is context-dependent. This is mouse overexpression biology and not a clinical result, but it is a concrete mechanistic reason the Crohn's readout may have reflected opposing cell-type effects rather than insufficient target engagement.

Abstract excerpt

Sphingosine 1-phosphate (S1P), a lipid mediator that signals through five G protein-coupled S1P receptors (S1PRs), regulates T cell trafficking, tissue residency, and inflammatory processes. In contrast to the established roles of S1P signaling in T cell trafficking, its role in neutrophil biology remains poorly understood. Here, we demonstrate that S1PR1, one of the two S1PRs expressed in neutrophils, promotes mitochondrial fitness, enhances survival, and reduces inflammatory output. Using myeloid- and neutrophil-selective S1PR1 overexpression (S1PR1hi) mouse models, we show that elevated S1PR1 signaling promotes redistribution of neutrophils from the bone marrow to peripheral tissues under steady-state conditions, without inducing overt inflammation or tissue injury. S1PR1hi neutrophils display altered surface marker profiles consistent with a less mature state. These cells also exhibit reduced in vivo turnover, increased mitochondrial membrane potential and oxidative phosphorylation, and transcriptional programs linked to survival and dampened inflammatory signaling. Functionally, S1PR1hi neutrophils exhibit a reduced oxidative burst while preserving phagocytic capacity. However, in vivo bacterial challenge revealed impaired bacterial clearance in the lung. In contrast, in a model of influenza A virus infection of the lung, enhanced neutrophil-intrinsic S1PR1 signaling conferred reduced lung injury, decreased inflammatory output, and improved survival. Together, these findings support a model in which S1PR1 reprograms neutrophils, enabling their survival and dampening inflammatory potential in a context-dependent manner, thereby differentially shaping host defense and tissue protection during microbial infections.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.