Platelet factors 4 produces an antidepressant effect in mice via inhibition of neuroinflammation

Introduction: Platelet Factor 4 (PF4) is secreted by platelets and can cross blood-brain barrier (BBB) to affect brain function, including regulations of neuroinflammation and synaptic plasticity, which are involved in the pathophysiology of depression. Nevertheless, whether PF4 participates in the development of depression has yet to be determined.

Objectives: The aim of this study was to investigate the role and the underlying mechanisms of PF4 in the pathophysiology of depression.

Methods: Mouse models of depression were established using chronic social defeat stress (CSDS) and lipopolysaccharide (LPS) paradigms. Plasma levels of PF4 and inflammatory cytokines were quantified by enzyme-linked immunosorbent assay (ELISA). A battery of behavioral tests were conducted to evaluate the effects of systemic and intra-nucleus accumbens (NAc) administration of PF4 siRNA or PF4 on depressive-like behaviors. RNA Sequencing (RNA-seq) for transcriptomic analysis and immunofluorescence staining were performed to assess neuroinflammatory status and microglial activation.

Results: Plasma PF4 was significantly reduced in patients with major depression. Similarly, CSDS mice exhibited decreased PF4 levels in both plasma and the NAc. Systemic PF4 administration produced an antidepressant-like effect in naive mice and rescued depressive-like behaviors in both CSDS and LPS-treated mice. In CSDS mice, intravenous administration of PF4 suppressed peripheral inflammatory response and increased PF4 levels in the NAc. Knockdown of PF4 in the NAc induced depressive-like behaviors in mice and markedly elevated inflammatory levels in this region. Correspondingly, infusion of PF4 into the NAc mitigated neuroinflammation, inhibited microglial activation, and alleviated depressive-like behaviors in CSDS mice. RNA-seq analysis also confirmed the suppressive effect of PF4 on neuroinflammatory pathways in the NAc.

Conclusion: Our findings demonstrate that PF4 exert an antidepressant effect, at least in part, by suppressing neuroinflammatory responses within the NAc. This work identifies PF4 as a novel and promising therapeutic target for the treatment of major depression.