RIPK3-MLKL dependent necroptosis mediates depressive-like behavior by facilitating neuroinflammation

Area of Science:

• Neuroscience
• Immunology
• Pharmacology

Background:

• Neuroinflammation is a key factor in depression, but its origins are not fully understood.
• Necroptosis, a pro-inflammatory cell death pathway, is implicated in inflammation.
• This study investigates the role of necroptosis-associated neuroinflammation in depression.

Purpose of the Study:

• To explore the involvement of necroptosis in depression.
• To investigate the therapeutic potential of targeting necroptosis in depression models.

Main Methods:

• Depression model mice were induced using lipopolysaccharide (LPS).
• Mice were treated with inhibitors of RIPK1 (Necrostatin-1s), RIPK3 (GSK’872), or MLKL (GW806742X).
• Behavioral tests, cytokine analysis, and molecular/histological assessments were performed.

Main Results:

• LPS-induced mice showed depressive behaviors, increased inflammatory cytokines, and enhanced MLKL phosphorylation.
• The RIPK3 inhibitor GSK’872 demonstrated significant antidepressant effects and ameliorated neuroinflammation.
• Inhibition of MLKL also improved depressive behavior and hippocampal neuroinflammation.

Conclusions:

• Hippocampal RIPK3-MLKL-dependent necroptosis mediates LPS-induced depressive behaviors.
• Necroptosis may promote neuroinflammation by releasing HMGB1.
• Targeting this pathway presents a potential therapeutic strategy for inflammatory depression.