Abstract
ABSTRACTMultiple sclerosis (MS) is a chronic disease that is characterized by demyelination and axonal damage in the central nervous system. Cognitive deficits are recognized as one of the features of MS, and these deficits affect the patients’ quality of life. Increasing evidence from experimental autoimmune encephalomyelitis (EAE), the animal model of MS, has suggested that EAE mice exhibit hippocampal impairment and cognitive deficits. However, the underlying mechanisms are still unclear. The NLRP3 inflammasome is a key contributor to neuroinflammation and is involved in the development of MS and EAE. Activation of the NLRP3 inflammasome in microglia is fundamental for subsequent inflammatory events. Activated microglia can convert astrocytes to the neurotoxic A1 phenotype in a variety of neurological diseases. However, it remains unknown whether the NLRP3 inflammasome contributes to cognitive deficits and astrocyte phenotype alteration in EAE. In this study, we demonstrated that severe memory deficits occurred in the late phase of EAE, and cognitive deficits were ameliorated by treatment with MCC950, an inhibitor of the NLRP3 inflammasome. In addition, MCC950 alleviated hippocampal pathology and synapse loss. Astrocytes from EAE mice were converted to the neurotoxic A1 phenotype, and this conversion was prevented by MCC950 treatment. IL-18, which is the downstream of NLRP3 inflammasome, was sufficient to induce the conversion of astrocytes to the A1 phenotype through the NF-κB pathway. IL-18 induced A1 type reactive astrocytes impaired hippocampal neurons through the release of complement component 3 (C3). Altogether, our present data suggest that the NLRP3 inflammasome plays an important role in cognitive deficits in EAE, possibly via the alteration of astrocyte phenotypes. Our study provides a novel therapeutic strategy for hippocampal impairment in EAE and MS.
Highlights
Multiple sclerosis (MS) is a chronic disease that is characterized by demyelination and axonal damage in the Official journal of the Cell Death Differentiation AssociationHou et al Cell Death and Disease (2020)11:377synapses[5,6,7]
No positive-signal of CD45 was found in the cortex or hippocampus of the EAE mice, which indicated that the Iba1-positive cells in the hippocampus of EAE mice might belong to resident microglia rather than macrophages infiltrating from peripheral (Fig. S2)
We found that the number of C3d (A1 reactive astrocytes marker) positive astrocytes and the level of C3d were increased in the EAE mice, whereas this increase was blocked by MCC950 (Fig. 4a, b, d)
Summary
Multiple sclerosis (MS) is a chronic disease that is characterized by demyelination and axonal damage in the Official journal of the Cell Death Differentiation AssociationHou et al Cell Death and Disease (2020)11:377synapses[5,6,7]. Multiple sclerosis (MS) is a chronic disease that is characterized by demyelination and axonal damage in the Official journal of the Cell Death Differentiation Association. Hou et al Cell Death and Disease (2020)11:377. Glial cells are necessary for hippocampal synaptic alterations and contextual learningmemory impairment in EAE6,8. It has been reported that the immune system and the CNS dynamically interact under pathological conditions and neuroinflammation has potential to influence longterm synaptic plasticity, the basis of memory[9]. The NLRP3 inflammasome is comprised of the NLR family, pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a carboxyterminal CARD (ASC), and pro-caspase-1. In the CNS, the NLRP3 inflammasome, IL1β and IL-18 are found in microglia[11,12,13] and take part in many diseases of the nervous system[14]. Nlrp3−/− mice are resistant to EAE and exhibit less immune cell infiltration[17]
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