Introduction
Multiple sclerosis(MS) is an inflammatory demyelinating autoimmune disease in the central nervous system(CNS) and it affects approximately 2.5 million people worldwide and poses a major burden to the healthcare system[1,2]. Current therapeutic options for MS include corticosteroids, beta interferon, immunosuppressive agents and monoclonal antibodies like anti-CD20[3], however, these treatments are effective only in some patients, and have significant adverse effects.
The pathogenesis of MS is unclear. Many studies have shown that both patient characteristics[4], and environmental factors such as intestinal flora imbalance and also gene–environment(GxE) interactions can affect the development of MS[5,6].
Previous studies on model of MS, experimental autoimmune encephalomyelitis(EAE), have shown that macrophages may play important roles in the pathophysiology of MS[7]. At the onset of EAE and MS, macrophages from peripheral tissues enter into the CNS, resulting in the pathological changes and M1 macrophage increased[8,9]. M2 macrophages can antagonize and inhibit the inflammation caused by inflammatory molecules related to M1 macrophages[10-12]. Previous studies have reported that M2 microglia can promote recovery of motor function after spinal cord injury in mice and delay the progression of EAE[13,14]. Macrophages are homologous to microglia and are easier to obtain and culture. Therefore, promotion of macrophage differentiation into M2 or enhancement of M2 macrophage are expected to be the novel strategies for the treatment of neuroinflammatory and immunological diseases in the future, which has attracted attention as a new method worldwide.
Nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κb), a protein complex mainly in the form of p50/p65 isodimers, is a key intracellular signal transduction molecule that can regulate the expression of many molecules involved in the early stage of immune and inflammatory responses[15,16]. NF-κb played an important role in the immune response of the nervous system, which began to increase on the 9th day after EAE induction in Lewis rats, peaked at the 11th and 12th days, and gradually decreased after the 14th day, and the dynamic changes of NF-κb activity were consistent with the EAE symptoms[17,18]. M2 macrophages can down-regulate the signal transduction of NF-κb, which may have therapeutic effects on EAE via inhibiting NF-κb activity[10].
BAY-11-7082(Beyotime) is a kind of NF-κb pathway blocker that can completely and specifically abolish NF-κb DNA binding, which also an irreversible inhibitor of TNF-α-induced inhibitor of NF-κb(IκB)-α phosphorylation that leading to NF-κb inactivation[19]. In the present study, we applied BAY-11-7082 in EAE mice to observe whether blocking NF-κb pathway can effectively alleviate the symptoms of EAE, and to explore the possible mechanisms behind the therapeutic role of BAY-11-7082 in EAE, in which investigation of its effect on macrophages is focused on.