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Bracchi-Ricard, V.

Publications and source records attributed to Bracchi-Ricard, V..

3 recordsLinked to original sources
bioRxiv2025

Hippocampal CA3 Nex/Neurod6+ neuron-specific TNFR2 alleviates chronic neuropathic pain by sex-dependently engaging opioid and endocannabinoid pathways

Chronic neuropathic pain (CNP) develops as a result of persistent neuroinflammation and maladaptive synaptic plasticity in the central nervous system following nerve injury. While tumor necrosis factor receptor 2 (TNFR2) signaling has been extensively studied in pain resolution, the expression of this receptor on specific neuronal populations and molecular pathways involved in spontaneous pain recovery still remains poorly defined. In this study, we investigated the role of TNFR2 signaling within hippocampal Nex/Neurod6 pyramidal neurons in promoting recovery from chronic constriction injury (CCI), a well-established rodent model of neuropathic pain. To achieve neuron-specific deletion of TNFR2, we generated tamoxifen-inducible conditional knockout mice (NexCreERT2:TNFR2F/F). We demonstrate that knocking out TNFR2 from Nex neurons prevents spontaneous pain recovery in both males and females. Thus, establishing that a supraspinal TNFR2 neuroimmune axis is necessary for pain recovery. Exogenous administration of a TNFR2 agonist at 7, 10, and 13 dpi (i.p.) significantly improved mechanical withdrawal thresholds in both sexes of wild-type mice but did not alleviate pain in Nex-specific TNFR2 knockouts, indicating that neuronal TNFR2 expression is required for TNFR2-mediated analgesia. Bulk RNA sequencing of hippocampal tissue collected at six weeks after CCI revealed that TNFR2 activation upregulates genes such as Pomc, involved in the opioid pathway, and oleoyl-ACP-hydrolase (OLAH), involved in the endocannabinoid pathway. Consistent with these findings, immunostaining and Western blot analyses showed that TNFR2 agonism restored cornu ammonis (CA3) region POMC and {beta}-endorphin protein levels that were otherwise suppressed after CCI. Behavioral experiment demonstrated that systemic blockade of the {micro}-opioid receptor with naltrexone (administered daily from 7-21 dpi (s.c.)) completely prevented TNFR2-mediated pain recovery in males but only partially in females. In contrast, inhibition of cannabinoid 1 receptor (CB1R) signaling with AM251 (administered at 7, 14, and 21 dpi (i.p.)) abolished TNFR2-driven analgesia in both sexes. Together, these results reveal that hippocampal TNFR2 signaling in Nex/Neurod6 neurons is critical in recovery from chronic neuropathic pain. TNFR2 activation promotes analgesia by engaging endogenous {beta}-endorphin/{micro}-opioid and endocannabinoid pathways in a sex-dependent manner, establishing TNFR2 agonism as a promising non-addictive therapeutic approach for chronic pain resolution. SignificanceChronic neuropathic pain (CNP) results from persistent neuroimmune signaling and is driven by maladaptive circuit plasticity. Due to the complexity of factors contributing to CNP, it often leaves patients with few treatment options, which, unfortunately, are either temporary or might be addictive. We have characterized a novel supraspinal mechanism through which tumor necrosis factor receptor 2 (TNFR2) signaling, specifically in hippocampal Neurod6/Nex+ expressing pyramidal neurons, is necessary for pain recovery following nerve injury. Pharmacological activation of TNFR2 in these neurons alleviates pain by engaging both endogenous opioid and endocannabinoid signaling pathways. We specifically demonstrate that TNFR2 agonism upregulates proopiomelanocortin (POMC) expression and {beta}-endorphin levels in the hippocampus. We further identify that pharmacological inhibition of either the -opioid receptor or cannabinoid 1 (CB1) receptor is sufficient to impair the effectiveness of TNFR2 agonist mediated pain resolution. Our findings thus uncover a novel neuroimmune mechanism where the TNFR2 agonist, exogenously activating the pro-resolving TNFR2, mitigates CNP by releasing endogenous pain neuromodulators. Here, we highlight that TNFR2 agonism could serve as a non-addictive therapeutic strategy for the resolution of chronic neuropathic pain.

pharmacology and toxicology↗
bioRxiv2024

Mitigating sTNF/TNFR1 activation on VGluT2+ spinal cord interneurons improves immune function after mid-thoracic spinal cord injury

Spinal cord injury (SCI) is a devastating condition with 250,000 to 500,000 new cases globally each year. Respiratory infections, e.g., pneumonia and influenza are the leading cause of death after SCI. Unfortunately, there is a poor understanding of how altered neuro-immune communication impacts an individuals outcome to infection. In humans and rodents, SCI leads to maladaptive changes in the spinal-sympathetic reflex (SSR) circuit which is crucial to sympathetic function. The cause of the impaired immune function may be related to harmful neuroinflammation which is detrimental to homeostatic neuronal function, aberrant plasticity, and hyperexcitable circuits. Soluble tumor necrosis factor (sTNF) is a pro-inflammatory cytokine that is elevated in the CNS after SCI and remains elevated for several months after injury. By pharmacologically attenuating sTNF in the CNS after SCI we were able to demonstrate improved immune function. Furthermore, when we investigated the specific cellular population which may be involved in altered neuro-immune communication we reported that excessive TNFR1 activity on excitatory INs promotes immune dysfunction. Furthermore, this observation is NF-kB dependent in VGluT2+ INs. Our data is the first report of a target within the CNS, TNFR1, that contributes to SCI-induced immune dysfunction after T9-SCI and is a potential avenue for future therapeutics.

neuroscience↗
bioRxiv2023

Increased activity of IRE1 improves the clinical presentation of EAE

Activation of the ER stress sensor IRE1 contributes to neuronal development and is known to induce neuronal remodeling in vitro and in vivo. On the other hand, excessive IRE1 activity is often detrimental and may contribute to neurodegeneration. To determine the consequences of increased activation of IRE1, we used a mouse model expressing a C148S variant of IRE1 with increased and sustained activation. Surprisingly, the mutation did not affect the differentiation of highly secretory antibody-producing cells, but exhibited a strong protective effect in a mouse model of experimental autoimmune encephalomyelitis (EAE). Significant improvement in motor function was found in IRE1C148S mice with EAE relative to WT mice. Coincident with this improvement, there was reduced microgliosis in the spinal cord of IRE1C148S mice, with reduced expression of pro-inflammatory cytokine genes. This was accompanied by reduced axonal degeneration and enhanced CNPase levels, suggestiing improved myelin integrity. Interestingly, while the IRE1C148S mutation is expressed in all cells, the reduction in proinflammatory cytokines and in the activation of microglial activation marker IBA1, along with preservation of phagocytic gene expression, all point to microglia as the cell type contributing to the clinical improvement in IRE1C148S animals. Our data suggest that sustained increase in IRE1 activity can be protective in vivo, and that this protection is cell type and context dependent. Considering the overwhelming but conflicting evidence for the role of the ER stress in neurological diseases, a better understanding of the function of ER stress sensors in physiological contexts is clearly needed.

neuroscience↗