Microglial cGAS-STING-TBK1 activation in paraventricular thalamus mediates sleep and emotional disturbances in lupus mice.

Sleep and emotional disturbances are prevalent in systemic lupus erythematosus (SLE) patients, yet the neuroinflammatory mechanisms remain unclear. Here, we investigated this issue using pristane-induced lupus (PIL) mice. We firstly confirmed that PIL mice exhibited progressive fragmentation of NREM sleep and decreased cumulative sleep time, correlating with blood-brain barrier (BBB) leakage and IgG deposition in the paraventricular thalamus (PVT). Concurrently, PVT neurons showed aberrant excitatory activity, including a high level of cFos expression, decreased amplitude and increased rate of Ca2+ transients during wakefulness. Bulk RNA sequencing and protein analyses demonstrated upregulation of the cyclic GMP-AMP synthase (cGAS) -stimulator of interferon genes (STING) -TANK-binding kinase 1 (TBK1) activation pathway in PVT microglia, with elevated phosphorylation of STING (pSTING) and TBK1 (pTBK1), promoting synthesis of pro-inflammatory cytokines. Selectively knockdown STING in microglia effectively normalized PVT neuronal excitability, restored sleep homeostasis, and ameliorated anxiety/depression-like behaviors. Notably, we identified selective expression of cannabinoid receptor type 2 (CB2R) in PVT microglia. Pharmacological CB2R activation could inhibit TBK1 phosphorylation, attenuate microglial inflammatory responses, and improve sleep and emotional disturbances. Our findings elucidate a novel neuroimmune axis in SLE-related neuropsychiatric symptoms, offering potential therapeutic avenues for mitigating neuroinflammation and associated behavioral comorbidities in lupus.