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

Initiation and resolution of inflammation are required to restore homeostasis. While neutrophils are classically viewed as short-lived effector cells that initiate inflammation, accumulating evidence suggests they can also contribute to resolution processes. Here, we identify neutrophil state characterized by long in vivo half-life, mitochondrial fitness, and reduced inflammatory output. Using myeloid- and neutrophil-restricted sphingosine 1-phosphate receptor-1 (S1PR1) overexpression mouse models (S1PR1hi), we show that elevated S1PR1 signaling is associated with redistribution of neutrophils from the bone marrow to peripheral tissues under steady-state conditions, without inducing overt inflammation or tissue injury. S1PR1hi neutrophils exhibit reduced turnover in vivo, increased mitochondrial membrane potential and oxidative phosphorylation, and transcriptional programs linked to survival and dampened inflammatory signaling. Despite reduced oxidative burst, these neutrophils retain phagocytic capacity and antibacterial activity. In a model of influenza A virus infection, enhanced neutrophil-intrinsic S1PR1 signaling correlates with reduced lung injury, decreased inflammatory output, and improved survival. Together, these findings support a model in which S1PR1 tunes neutrophil persistence and inflammatory potential, thereby shaping immune responses during infection and tissue repair. One Sentence SummaryS1PR1 signaling biases neutrophils toward a persistent, metabolically supported state with reduced inflammatory output that promotes recovery from viral lung injury.