Chronic pain is defined as any consistent pain lasting more than 12 weeks; chronic pain afflicts 25% of the world' s population. The most common form of chronic pain is chronic neuropathic pain, which affects around 8% of the general population and is defined as pain that is initiated or caused by a primary lesion or dysfunction of the nervous system. Neuropathic pain is commonly associated with a variety of neurodegenerative, metabolic, and autoimmune diseases. In multiple sclerosis (MS), chronic neuropathic pain is one of the most frequent symptoms that dramatically reduces the quality of life of MS patients. Current treatment strategies include antidepressants, anticonvulsants, and cannabinoid drugs. However, the efficacy of these drugs varies between patients. Besides providing only insufficient relief of pain, these drugs also lead to severe side effects. Therefore, there is an unmet medical need to identify novel drug targets, which may lead to the development of novel therapeutics with enhanced tolerability profiles and efficacy for the management of MS-associated chronic neuropathic pain. Neuropathic pain in multiple sclerosis 54

Tumor necrosis factor receptor 2 (TNFR2) is a transmembrane receptor that promotes immune modulation and tissue regeneration and is recognized as a potential therapeutic target for multiple sclerosis (MS). However, TNFR2 also contributes to T effector cell function and macrophage-TNFR2 recently was shown to promote disease development in the experimental autoimmune encephalomyelitis (EAE) model of MS. We here demonstrate that systemic administration of a TNFR2 agonist alleviates peripheral and central inflammation, and reduces demyelination and neurodegeneration, indicating that protective signals induced by TNFR2 exceed potential pathogenic TNFR2-dependent responses. Our behavioral data show that systemic treatment of female EAE mice with a TNFR2 agonist is therapeutic on motor symptoms and promotes long-*

Early TLR4 blockade protects islets from sterile inflammation-mediated stress sustained during isolation and promotes positive transplant outcomes. Our findings support the use of early TLR4 blockade during clinical islet isolation procedures to reduce pretransplant inflammation and improve transplant outcomes.

Multiple sclerosis is an autoimmune disorder of the central nervous system (CNS) characterized by locomotor impairments, cognitive deficits, affective disorders, and chronic pain. Females are predominately affected by MS compared to males and develop motor symptoms earlier. However, key symptoms affect all patients regardless of sex. Previous studies have shown that demyelination and axonal damage play key roles in symptom development, but it is unclear why sex differences exist in MS onset, and effective symptom treatment is still lacking. We here used a non-pertussis toxin (nPTX) experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice, to explore chronic symptoms and sex differences in CNS autoimmunity. We observed that, like in humans, female mice developed motor disease earlier than males. Further, changes in pre-and post-synaptic protein expression levels were observed in a sexually dimorphic manner with an overall shift towards excitatory signaling. Our data suggest that this shift towards excitatory signaling is achieved through different mechanisms in males and females. Altogether, our study helps to better understand sex-specific disease mechanisms to ultimately develop better diagnostic and treatment tools.

No abstract