Fluvoxamine attenuates inflammation in experimental sepsis via novel non-canonical pathways.

Sepsis is characterized by a dysregulated systemic inflammatory response to infection and remains a major global health challenge, underscoring the need for novel therapeutic strategies. Drug repurposing offers a promising strategy, and fluvoxamine (FLV), a selective serotonin reuptake inhibitor (SSRI) widely used in psychiatric treatment, has been reported to exhibit anti-inflammatory properties. Here, we investigated the effects of FLV in a murine model of sepsis induced by cecal ligation and puncture (CLP). Oral pretreatment with FLV for seven days significantly increased the anti-inflammatory cytokine IL-10 in both plasma and peritoneal fluid, without affecting proinflammatory cytokines IL-6 and IL-1β. Conversely, when evaluating the involvement of the central nervous system through intracerebroventricular administration of FLV, a broad reduction in circulating cytokines was observed, encompassing both pro- and anti-inflammatory mediators. In vitro, FLV suppressed inflammatory cytokine production in LPS-stimulated macrophages, indicating a direct effect on immune cells. Notably, these immunomodulatory effects were independent of serotonin signaling and sigma-1 receptor activation, pathways traditionally associated with SSRI mechanisms. We demonstrate that FLV modulates cytokine production through distinct central and peripheral mechanisms. Our findings provide new insights into the immunomodulatory actions of FLV and support its potential repurposing as an adjunctive therapy for inflammatory diseases such as sepsis.