FPR2 deficiency alleviates LPS-induced depressive-like behaviors in mice by suppressing microglial CSF1/NLRP3 inflammasome

Depression is a highly prevalent psychiatric disorder with complex and poorly understood pathogenesis. Emerging evidence points to neuroinflammation as a critical contributor, particularly involving microglial activation and the NLRP3 inflammasome. Current antidepressant therapies often have limited efficacy or significant side effects, highlighting the need for novel therapeutic targets. Formyl peptide receptor 2 (FPR2) is a key regulator of innate immunity and inflammation, but its specific role in neuroinflammation-driven depressive states, especially concerning microglial function and the NLRP3 inflammasome pathway, remained largely unexplored. This study investigates FPR2's involvement in LPS-induced depression to identify potential new intervention strategies.

Researchers investigated the role of FPR2 in lipopolysaccharide (LPS)-induced depressive-like behaviors in mice. They used Fpr2-/- (FPR2 knockout) mice and wild-type controls, administering LPS intraperitoneally to induce neuroinflammation and behavioral changes. The study assessed depressive and anxiety-like behaviors using standard rodent tests. Microglial activation and FPR2 expression were quantified in the prefrontal cortex (PFC) and hippocampus. RNA sequencing and subsequent validation experiments (qPCR, ELISA) were performed on microglial cells to analyze NLRP3 inflammasome activation and IL-1β levels. The regulatory mechanisms involving CSF1 and serum amyloid A (SAA) were also explored.

FPR2 deficiency (Fpr2-/-) significantly attenuated LPS-induced depressive and anxiety-like behaviors in mice, demonstrating a protective role. LPS challenge markedly increased FPR2 expression in microglia of the PFC and hippocampus, with only minimal changes in neurons. FPR2 deficiency also alleviated LPS-induced microglial activation and reduced neuronal synaptic alterations, suggesting a broader neuroprotective effect. RNA sequencing and validation confirmed that FPR2 deletion substantially decreased LPS-induced microglial NLRP3 inflammasome activation and IL-1β levels in the brain. Mechanistically, FPR2 regulated downstream NLRP3 activation by modulating CSF1, and the FPR2/CSF1 activation was governed by its upstream ligand, serum amyloid A (SAA).