CNS inflammation is a major driver of MS pathology. Differential immune responses, including the adaptive and the innate immune system, are observed at various stages of MS and drive disease development and progression. Next to these immune-mediated mechanisms, other mediators contribute to MS pathology. These include immune-independent cell death of oligodendrocytes and neurons as well as oxidative stress-induced tissue damage. In particular, the complex influence of oxidative stress on inflammation and vice versa makes therapeutic interference complex. All approved MS therapeutics work by modulating the autoimmune response. However, despite substantial developments in the treatment of the relapsing-remitting form of MS, approved therapies for the progressive forms of MS as well as for MS-associated concomitants are limited and much needed. Here, we summarize the contribution of inflammation and oxidative stress to MS pathology and discuss consequences for MS therapy development.

Tumor necrosis factor receptor 2 (TNFR2) activation is a promising-therapeutic strategy for autoimmune disorders such as multiple sclerosis (MS) and chronic neuropathic pain (CNP). This study aimed to identify mechanisms governing the sex-specific efficacy of TNFR2 activation on abrogating pain and motor disease severity in mice experiencing experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. We find that the XX sex-chromosome complement is indispensable for TNFR2-mediated attenuation of EAE-associated motor disease. Mice with XY chromosomes experienced exacerbated motor disease severity, associated with an elevated magnitude of neurodegeneration and demyelination. Contrasting this, we show that TNFR2-mediated alleviation of EAE induced CNP is both sex and sex-chromosome independent. However, the alleviation of CNP following TNFR2 activation across two different neuropathic pain models (EAE and chronic constriction injury) was dependent on the gonadal hormone Activin-A. This suggests a shared mechanism through which gonadal-derived factors impact TNFR2-mediated pain relief, independent of sex hormones. These findings highlight the importance of considering sex chromosomes and sex-independent gonadal hormones in evaluating potential sex-specific differences in drug efficacy during therapeutic development.

The rat mid-thoracic contusion model has been used to study at-level tactile allodynia after spinal cord injury (SCI), one of the more common types of allodynia. An important advantage of this model is that not all animals develop allodynia and, therefore, it could be used to more clearly examine mechanisms that are strictly related to pain development separately from mechanisms related to the injury itself. However, how to separate those that develop allodynia from those that do not is unclear. The aims of the current study were to identify where allodynia and spasticity develop and use this information to identify metrics that separate animals that develop allodynia from those that do not in order study difference in their behavior. To accomplish these aims, a standardized grid was used to localize pain on the dorsal trunk and map it to thoracic dermatomes, providing for the development of a pain score that relied on supraspinal responses and separated subgroups of animals. Similar to human studies, the development of allodynia often occurred with the development of spasticity or hyperreflexia. Moreover, the time course and prevalence of pain phenotypes (at-, above-, or below level) produced by this model were similar to that observed in humans who have sustained an SCI. However, the amount of spared spinal matter in the injured cord did not explain the development of allodynia, as was previously reported. This approach can be used to study the mechanism underlying the development of allodynia separately from mechanisms related to the injury alone.

Chronic low-grade inflammation is increasingly recognized as a key driver of heart failure (HF) progression; however, the direct contribution of systemic inflammatory disorders such as osteoarthritis (OA) remains unclear. Here, we establish a murine model of OA-induced HF using destabilization of the medial meniscus (DMM) to induce systemic inflammation and sex-specific cardiac remodeling. Longitudinal echocardiography revealed that females develop diastolic dysfunction with preserved ejection fraction, resembling HFpEF, whereas males exhibit progressive systolic impairment, consistent with a transitional HFmrEF-to-HFrEF phenotype. Morphometric and histological analyses confirmed concentric hypertrophy in females and eccentric remodeling in males. Transcriptomic profiling identified distinct molecular programs: females upregulated extracellular matrix, cytoskeletal, and calcium-handling genes, while males showed enrichment of inflammatory and immune signaling pathways. Immunoblot analyses further validated these sex-specific molecular signatures: females displayed increased ANP, BNP, Sirt1, and AMPK expression, consistent with metabolic resilience and fibrotic remodeling, whereas males exhibited elevated p38 MAPK, NF-κB, LC3B, and cleaved caspase-3, reflecting heightened inflammation, autophagy, and apoptosis. Both sexes demonstrated downregulation of mitochondrial and lipid metabolic proteins, indicating convergent energetic stress. Collectively, these findings identify OA as a systemic inflammatory driver of heart failure, delineate the molecular and proteomic basis of sex-dependent cardiac remodeling, and introduce a translational preclinical model that recapitulates the clinical heterogeneity of HFpEF and HFmrEF/HFrEF, providing a foundation for mechanistic and therapeutic exploration.

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 (NexCre ^{ERT 2} :TNFR2 ^F/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 β-endorphin protein levels that were otherwise suppressed after CCI. Behavioral experiment demonstrated that systemic blockade of the µ-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 β-endorphin/µ-opioid and endocannabinoid pathways in a sex-dependent manner, establishing TNFR2 agonism as a promising non-addictive therapeutic approach for chronic pain resolution. Significance: Chronic 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 β-endorphin levels in the hippocampus. We further identify that pharmacological inhibition of either the μ-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.