S1PR1 signaling biases neutrophils toward long-lived low-inflammatory functional states

Abstract

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.