Abstract
Reactive microglia are suggested to be involved in neurological disorders, and the mechanisms underlying microglial activity may provide insights into therapeutic strategies for neurological diseases. Microglia produce immunological responses to various stimuli, which include fractalkine (FKN or CX3CL1). CX3CR1, a FKN receptor, is present in microglial cells, and when FKN is applied before lipopolysaccharide (LPS) administration, LPS-induced inflammatory responses are inhibited, suggesting that the activation of the FKN signal is beneficial. Considering the practical administration for treatment, we investigated the influence of FKN on immunoreactive microglia using murine primary microglia and BV-2, a microglial cell line. The administration of LPS leads to nitric oxide (NO) production. NO was reduced when FKN was administered 4 h after LPS administration without a change in inducible nitric oxide synthase expression. In contrast, morphological changes, migratory activity, and proliferation were not altered by delayed FKN treatment. LPS decreases the CX3CR1 mRNA concentration, and the overexpression of CX3CR1 restores the FKN-mediated decrease in NO. CX3CR1 overexpression decreased the NO production that is mediated by LPS even without the application of FKN. ATP and ethanol also reduced CX3CR1 mRNA concentrations. In conclusion, the delayed FKN administration modified the LPS-induced microglial activation. The FKN signals were attenuated by a reduction in CX3CR1 by some inflammatory stimuli, and this modulated the inflammatory response of microglial cells, at least partially.
Highlights
Microglia are immune cells present in the central nervous system
It has been reported that FKN attenuates pro-inflammatory microglial activity [25,26,27], it is unclear whether FKN suppresses the activity of reactive microglia
We examined the effect of FKN on nitric oxide (NO) production in a microglial cell line, BV-2, and a similar tendency was observed (Fig 1C)
Summary
Microglia are immune cells present in the central nervous system. Evidence has indicated that microglia are associated with neuropsychiatric disorders, including schizophrenia and chronic neurodegenerative disorders such as amyotrophic lateral sclerosis. Findings have further suggested the involvement of microglia in other pathophysiological events such as the formation of neuropathic pain and synaptic remodeling [1,2,3,4]. Reactive microglia are observed with in vivo PET tracers in psychiatric patients [5], and the regulation of microglial activity is expected to become a therapeutic target soon. Microglia become pro-inflammatory following various forms of stimulation, which results in the upregulation of inflammatory.
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