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Repetitive opioid treatment promotes analgesic tolerance through mechanisms involving opioid-induced neuroinflammation. Here, we report that Wnt signaling activation can rescue opioid analgesic effects and suppress neuroinflammation by regulating microglial cells in the spinal cord. We used prolonged repetitive morphine treatment (10 mg/kg, daily) to induce morphine analgesic tolerance in adult C57BL/6J mice. Experiments were performed in mice and in the BV-2 microglial cell line to determine the potential cellular mechanisms underlying the effects of recombinant Wnt3a on microglial reactive states. Our in vivo studies showed that repetitive morphine treatment suppressed the level of Wnt ligands and β-catenin activity in the spinal cord. After 4 days of repetitive morphine treatment, intrathecal administration of Wnt3a rescued the analgesic effect of morphine. Ablation of the microglial population by PLX5622 revealed that microglial cells were required for Wnt3a to restore the analgesic efficacy of morphine. In vitro results indicated that exogenous Wnt3a inhibited neuroinflammation and regulated the reactive states of microglial cells by suppressing the activity of NF-κB and increasing the nuclear expression of STAT3. These findings demonstrate that Wnt3a signaling activation can rescue the analgesic effect of morphine and suppress morphine tolerance-induced neuroinflammation by regulating microglial reactivation in the spinal cord. This study provides mechanistic insights into the pathophysiology of morphine tolerance and potential therapeutic targets to control morphine-induced neuroinflammation.

Microglia make important contributions to central nervous system (CNS) development, but the breadth of their distinct developmental functions remains poorly understood. The mouse retina has been a key model system for understanding fundamental mechanisms controlling the assembly of the CNS. To gain insight into where and how microglia might influence retinal development, here we identified molecularly unique myeloid cell populations that are selectively present during development and characterized their anatomical locations. Development-specific transcriptional states were identified using single-cell (sc) and single-nucleus RNA-sequencing (RNA-seq) across multiple timepoints. Transcriptional states were validated in vivo by histological staining for key RNA and/or protein markers. Several of these development-specific myeloid populations have been described before in brain scRNA-seq atlases but not validated in vivo, while others are unique to our retinal dataset. We identify two closely related microglial populations, labeled by the Spp1 and Hmox1 genes, that are distinguished mainly by transcriptional targets of the NRF2 transcription factor. Both types are present selectively within the developing retinal nerve fiber layer where they engulf neurons and astrocytes undergoing developmental cell death. Hmox1⁺ microglia were also localized selectively at the wavefront of developing vasculature during retinal angiogenesis, suggesting that developmental events associated with angiogenesis modulate NRF2 activity and thereby induce microglia to switch between the Spp1⁺ and Hmox1⁺ states. Overall, our results identify transcriptional profiles that define specific populations of retinal microglia, opening the way to future investigations of how these programs support microglial functions during development.

Exposure to hypoxic environments leads to neurological dysfunction, with recent studies implicating microglia-derived neuroinflammation involved in hypoxia-induced neuronal impairment. However, the underlying pathological mechanisms remain largely unclear. Lipid-droplet-accumulating microglia (LDAM) have been linked to age-related and genetic forms of neurodegeneration, prompting the investigation of their role in hypoxia-induced neuronal impairment. In this study, we observed that hypoxia induced lipid droplets accumulation in microglia, accompanied by increased levels of RETSAT, an enzyme involved in lipid metabolism regulation. Conditional knockout of RETSAT in microglia decreased lipid droplets accumulation and alleviates hypoxia-induced microglial-derived neuroinflammation and oxidative stress, both in vitro and in vivo. Our biological studies indicate that the beneficial effects of RETSAT knockout on lipid droplets degradation are primarily mediated through enhanced activity of hormone-sensitive lipase (HSL). Furthermore, we found that the hypoxic adaptation-related RETSAT mutation Q247R promotes microglia lipolysis under hypoxic conditions. These findings suggest that RetSat is a potential therapeutic target for the prevention and treatment of hypoxia-induced microglial activation.

Astrocyte senescence plays an essential role in CNS disorders. However, the understanding of astrocyte senescence and its regulatory targets in hepatic encephalopathy (HE) is limited. SGK1 was reported to regulate astrocyte senescence. Therefore, the current study aimed to investigate the role of SGK1 and astrocyte senescence in HE. The rat model of HE was established by common bile duct ligation. Adeno-associated virus (AAV) was used for astrocyte-specific knockdown of SGK1. The rats were also evaluated with behavioral tests. Primary rat astrocytes were used for in vitro validation. RNA-sequencing was used to further investigate the underlying mechanisms. SGK1 was significantly upregulated in HE, especially in astrocytes. Cellular senescence was enriched in the expression profiles of the brain from HE patients, when senescence-associated secretory phenotype (SASP) and mitochondrial dysfunction were also activated in astrocytes from the rat model of HE. Knockdown of astrocyte SGK1 ameliorated HE by alleviating cellular senescence and mitochondrial dysfunction, when the underlying mechanisms were tightly associated with interferon response. Alleviated astrocyte SASP by SGK1 knockdown further protected against neuroinflammation by suppressing microglia activation and pro-inflammatory polarization. The effects of SGK1 on astrocyte senescence were mediated by the IL-6/JAK2/STAT3 signaling pathway. SGK1 inhibition improved HE by ameliorating astrocyte senescence and mitochondrial dysfunction. SGK1 and the downstream IL-6/JAK2/STAT3 signaling pathway might be novel therapeutic targets for the treatment of HE.

Oligodendrocytes (OLs) generate myelin sheaths around axons and maintain them to facilitate the propagation of action potentials and support neuronal metabolism and synaptic function. Previously, we have shown that Fibroblast Growth Factor Receptor-1 and -2 (FGFR1/2) signaling is required for oligodendrocyte precursor cell (OPC) expansion, promoting myelin growth during developmental myelination and maintaining myelin/axonal integrity in the spinal cord during adulthood. However, whether OL-lineage cells may affect neuronal synaptic functions and impact memory/learning during adulthood/aging remained largely unknown. Here, we showed that FGFR1/2 signaling in OPCs and OLs is required throughout adulthood and is critical for the long-term maintenance of synaptic activity and memory. Specifically, the lack of FGFR1/2 signaling within OL-lineage cells resulted in the impairment of long-term potentiation (LTP), a reduction in docked synaptic vesicles at the synaptic terminals, deficits in hippocampal-based memory and learning, and β-APP accumulation in older animals. Importantly, we found that there was no loss of OPCs or OLs, myelin degeneration, astrogliosis, microglial activation, or reduction in myelin thickness in the adult hippocampus of mutant mice. Furthermore, the tamoxifen-inducible loss of FGFR1/2 signaling during adulthood also impaired LTP. In addition, the conditional ablation of either FGFR1 or FGFR2 individually in the OL-lineage cells impaired LTP during adulthood, although at different levels. Thus, these observations bring up the possibility that FGFR1/2 signaling in OL-lineage cells may play a potentially novel, previously unrecognized role in OL-neuron communication for the maintenance of synaptic plasticity and memory functions in the normal adult/aging brain.

Neuropathic pain, a persistent condition arising from injury to the nervous system, involves complex interactions between neurons and non-neuronal cells, including satellite glial cells (SGCs) in the dorsal root ganglia (DRG). In this study, we examined the glial-targeting effects of meteorin, a neurotrophic protein with gliogenic properties, using mouse models of neuropathic and inflammatory pain. Systemic meteorin administration reversed mechanical hypersensitivity across diverse neuropathic and inflammatory pain models, with therapeutic effects persisting beyond the treatment period. We identified SGCs as the principal site of meteorin expression and action in the DRG, where it selectively activated SGCs and altered their functional state. Proteomic profiling revealed meteorin-mediated downregulation of gap junction proteins in SGCs, particularly connexin 43, which was corroborated by immunohistochemical analyses. Functional assessments demonstrated that meteorin treatment normalized injury-induced increases in intercellular coupling between SGCs, establishing a mechanistic link between glial network modulation and pain resolution. These findings identify meteorin as a regulator of SGC communication through connexin-dependent mechanisms. The sustained therapeutic effects and multi-model efficacy highlight meteorin as a potential intervention for neuropathic pain while advancing our understanding of SGC plasticity in sensory processing.

ELAVL1 is known to regulate mRNA stability in various diseases, but its role in ferroptosis and Schwann cell dysfunction in diabetic peripheral neuropathy (DPN) has not been previously explored. This study investigates the mechanistic role of ELAVL1 in Schwann cell ferroptosis and explores the therapeutic potential of bone marrow-derived mesenchymal stem cells (BMSCs) in alleviating DPN. We used a streptozotocin (STZ)-induced diabetic mouse model and high-glucose-treated Schwann cells to study DPN-associated neuropathy, oxidative stress, and ferroptosis. ELAVL1 expression was analyzed in DPN patients and diabetic mice. A Schwann cell-specific ELAVL1 knockout (ELAVL1-KO) mouse model was developed to assess its impact on nerve function and oxidative stress. Mechanistic studies examined ELAVL1 interaction with ACSL4 mRNA in ferroptosis. Finally, BMSCs were administered at different doses to evaluate their effects on the ELAVL1/ACSL4 pathway. We found that ELAVL1 was significantly upregulated in the sciatic nerves of DPN patients and STZ-induced DPN mice. ELAVL1 co-localized with Schwann cells and contributed to myelin damage, oxidative stress, and ferroptosis. Knockdown of ELAVL1 in Schwann cells improved sciatic nerve conduction, reduced oxidative stress, and restored myelin integrity in DPN mice. Mechanistically, ELAVL1 promoted ferroptosis by binding to the 3′-UTR of ACSL4 mRNA, thereby stabilizing ACSL4 expression. Notably, BMSC therapy downregulated ELAVL1 and ACSL4 expression in a dose-dependent manner, reducing oxidative stress, iron accumulation, and ferroptosis. In conclusion, ELAVL1 promotes Schwann cell ferroptosis in DPN via ACSL4 mRNA stabilization. Furthermore, BMSC therapy reduces ferroptosis by modulating the ELAVL1/ACSL4 axis, offering a promising approach for DPN treatment.

Microglia are unique damage sensors of the central nervous system, and their homeostatic roles are increasingly recognized. Purinergic signaling through the P2Y12 receptor (P2Y12R) is indispensable for directed process movement of microglia in response to danger-related ATP release. P2Y12R has also been shown to modulate microglial communication with neurovascular elements in the brain and to profoundly influence outcomes in experimental models of brain injury. However, the exact role of P2Y12R in shaping microglial phenotypes and interactions under physiological conditions remains unresolved due to disagreements between ex vivo and in vivo observations. Using in vivo 3D two-photon imaging and high-resolution anatomy we show that P2Y12Rs are essential regulators of microglial physiology, fundamentally shaping homeostatic microglial surveillance activity and direct contacts with other cell types. Genetic deletion or acute pharmacological blockade of P2Y12R function leads to altered surveillance activity, microglial morphology and P2Y12R nanoclustering, resulting in changes of direct microglial contacts with neuronal cell bodies, smooth muscle-bearing blood vessels and oligodendrocyte processes in the somatosensory cortex of mice. Furthermore, molecular anatomy of P2Y12R expression shows correlation with disease severity and altered microglia–neuron interactions in human epilepsy. Thus, our results identify P2Y12Rs as major participants in microglial physiology whose dysfunction could impact defined cell–cell interactions in different neurological states.