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.