Journal of Neuroinflammation最新文献

Background: Major depressive disorder (MDD) remains a debilitating global health issue with limited treatment efficacy. Liver qi stagnation (or called liver depression) has been associated with MDD, but the underlying mechanisms are poorly understood. This study investigates whether impaired hepatic function contributes to depressive symptomatology.

Methods: Using retrospective clinical data, chronic unpredictable stress (CUMS) models, orthotopic liver transplantation, and microglia-specific genetic tools (including TRPM2 and SYK conditional knockouts), we combined behavioral assays, multi-omics, electrophysiology, and optogenetics to explore the liver-brain axis in depression.

Results: Compromised hepatic bilirubin clearance in depressive subjects drives depressive symptoms by enhancing microglial engulfment of dendritic spines in the anterior cingulate cortex (ACC). Clinical evidence highly reveals a correlation between hyperbilirubinemia and MDD severity, mirrored in chronic stress mouse models. Liver transplantation from stressed to non-stressed mice impaired bilirubin clearance and induced depressive behaviors, accompanied by ACC glutamatergic neuronal hypoactivity (ACC^Glu) and microglial overactivation. Conversely, transplanting healthy livers into stressed mice alleviated these symptoms. Mechanistically, hyperbilirubinemia activates the bilirubin-TRPM2-SYK axis in microglia, promoting excessive spine pruning and synaptic loss in ACC^Glu by employing transcriptional pause-release mechanisms to prioritize protein synthesis of pro-phagocytosis machines. Pharmacological inhibition or genetic ablation of microglial TRPM2 rescues spine density and depressive behaviors. And the maladaptation of ACC^Glu neurons in hyperbilirubinemic mice was reversible by TRPM2 blockade, either.

Conclusion: Our results reveal a novel liver-brain pathway whereby impaired bilirubin clearance drives depression via microglial synaptic pruning. Targeting microglial TRPM2 offers a promising therapeutic strategy for MDD.

Infections in the central nervous system result in immune cell trafficking into the brain and microglial activation, which may influence Alzheimer's Disease neuropathology. Toxoplasma gondii infection induces a robust neuroimmune response and a reduction in amyloid plaques in the brains of Alzheimer's model mice. We investigated the myeloid cell response in the immediate vicinity of amyloid plaques in the brain by injecting 3-month-old 5xFAD mice with T. gondii or PBS as a control. T. gondii chronic infection (6 weeks) resulted in reduced amyloid plaque area, volume, and intensity in the cortex, and plaques with decreased circularity based on 6E10 and Thio-S staining. The brains of T. gondii-infected mice also had increased AIF1, AXL, and CLEC7A transcripts for disease-associated microglia (DAM), and elevated IBA1, MAC2, and CD68 phagolysosomal colocalization with amyloid, indicating myeloid cell activation around plaques. CD4 and CD8 T cells were also increased near amyloid and IBA1⁺ cells in T. gondii-infected mice. To determine the extent of peripheral myeloid cell recruitment to amyloid, bone marrow from CAG-CFP mice was transplanted into irradiated, head-shielded 5xFAD mice prior to infection. Cyan⁺ cells were found surrounding plaques in the brains of T. gondii-infected mice and were comprised predominantly of Ly6C^lo patrolling monocytes, followed by Ly6C^hi inflammatory monocytes and T cells. In addition, the majority of myeloid cells and T cells recruited to the brain were derived from skull bone marrow. These data demonstrate that T. gondii infection increases the infiltration of monocytes and T cells from the skull bone marrow niche and the recruitment of highly activated myeloid cells surrounding amyloid plaques in the brains of 5xFAD mice.

Retinitis pigmentosa (RP), the most prevalent inherited retinal degenerative disorder, manifests as progressive and irreversible photoreceptor loss with no approved disease-modifying therapies. Emerging evidence implicates microglia-mediated neuroinflammation as a critical accelerator of RP progression, but its underlying molecular mechanisms remain elusive. Through single-cell RNA sequencing (scRNA-seq) of retinal microglia from the rd10 mouse model of RP, we identified Ccl7 as an important driver of microglial inflammation and defined a distinct subpopulation of CCL7hi microglia as pivotal orchestrators of neuroinflammation and photoreceptor degeneration. Evidently, genetic knockdown of Ccl7 suppressed microglial activation and neuroinflammation, attenuated photoreceptor degeneration, and preserved visual function in rd10 mice, while exogenous CCL7 administration exacerbated microglial reactivity and accelerated photoreceptor apoptosis. Ccl7 upregulation in microglia induced a characteristic senescent signature and promoted pathological phagocytosis, contributing to inflammation and photoreceptor cell death. Mechanistically, microglial Ccl7 trigger a self-amplifying inflammatory cascade by activating STAT1 signaling, and propagate inflammation cascades through CCL7-CCR1/5 inter-microglial communication. Our results establish the CCL7-STAT1 axis as an important regulator of microglial dysfunction in RP. Targeting this pathway represents a promising disease-modifying strategy to halt RP progression, with significant implications for clinical translation.