Abstract
BackgroundDemyelinating disease of the central nervous system is one of the most common neurological diseases and effective treatment is still under in-depth research. Our previous study showed that Angiostrongylus cantonensis infection can induce demyelination injury in mouse brains and IL-17A expression was shown to be significantly increased during this process. Moreover, we found that IL-17A inhibition attenuated the demyelination caused by A. cantonensis infection. However, the underlying mechanisms have not yet been fully elucidated.MethodsIL-17A neutralizing antibodies were injected into A. cantonensis infected mice to decrease IL-17A levels. The activation of glial cells in the brain and the expression of cell markers were detected by a variety of methods, including real-time quantitative PCR, western blotting, and immunofluorescence staining. The relationship between IL-17A and astrocyte activation was further identified by in vitro experiments. The role of SOCS3 in the IL-17A stimulating process was determined using RNA-seq data collection of infected mice and the siRNA interference method.ResultsDemyelination of the corpus callosum was relieved after administration of IL-17A neutralizing antibody and this was accompanied by decreased activation of A1 type astrocytes around this region. The expression of SOCS3 was attenuated and activation of astrocytes by IL-17A was mediated by the IL-17RA/STAT3/SOCS3 pathway. IL-17A not only directly damaged oligodendrocytes but also indirectly damaged oligodendrocytes through A1 astrocyte mediation. Specific siRNA inhibition of IL-17A-inducible SOCS3 in astrocytes alleviated their damaging effects on oligodendrocytes.ConclusionIL-17A plays an important role in demyelination induced by A. cantonensis infection via the IL-17RA/STAT3/SOCS3 pathway in A1-type astrocytes, indicating that specific blockage of IL-17A and SOCS3 activity could be a therapeutic strategy for neuroinflammatory demyelinating diseases associated with astrocyte activation.
Highlights
Angiostrongyliasis is a food-borne parasitic disease caused by infection with Angiostrongylus cantonensis, a parasite found mostly in coastal areas
Immunofluorescence staining results showed that the number of astrocyte positive cells (C3d+ GFAP+, S100a10+ GFAP+) increased significantly at 14 dpi (Figures 2A, B). These results indicated that both A1 and A2 astrocytes were highly activated after A. cantonensis infection and that the activation of astrocytes was mainly concentrated in the corpus callosum region
Our results showed that the increase of IL-17A induced by A. cantonensis infection caused myelin sheath injury and activated astrocytes, with both A1 and A2 astrocytes being activated to varying degrees
Summary
Angiostrongyliasis is a food-borne parasitic disease caused by infection with Angiostrongylus cantonensis, a parasite found mostly in coastal areas. The clinical manifestations of infection are headache, neck stiffness, vomiting, and fever and the pathological changes are mainly meningitis and meningoencephalitis characterized by increased eosinophils [3]. If antiparasitic drugs are used alone in the late stage of infection, the disintegration products released after the death of A. cantonensis can induce a secondary severe inflammatory response in the brain tissue, aggravating the damage to the brain tissue [4]. Investigating the pathological mechanism of A. cantonensis infection and optimizing the treatment is still a focus for researchers. Our previous study showed that Angiostrongylus cantonensis infection can induce demyelination injury in mouse brains and IL-17A expression was shown to be significantly increased during this process. We found that IL-17A inhibition attenuated the demyelination caused by A. cantonensis infection. The underlying mechanisms have not yet been fully elucidated
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