TNF-α Triggers RIP1/FADD/Caspase-8-Mediated Apoptosis of Astrocytes and RIP3/MLKL-Mediated Necroptosis of Neurons Induced by Angiostrongylus cantonensis Infection
Open Access
- 8 March 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cellular and Molecular Neurobiology
- Vol. 42 (6), 1841-1857
- https://doi.org/10.1007/s10571-021-01063-w
Abstract
Angiostrongylus cantonensis (AC) can cause severe eosinophilic meningitis or encephalitis in non-permissive hosts accompanied by apoptosis and necroptosis of brain cells. However, the explicit underlying molecular basis of apoptosis and necroptosis upon AC infection has not yet been elucidated. To determine the specific pathways of apoptosis and necroptosis upon AC infection, gene set enrichment analysis (GSEA) and protein–protein interaction (PPI) analysis for gene expression microarray (accession number: GSE159486) of mouse brain infected by AC revealed that TNF-α likely played a central role in the apoptosis and necroptosis in the context of AC infection, which was further confirmed via an in vivo rescue assay after treating with TNF-α inhibitor. The signalling axes involved in apoptosis and necroptosis were investigated via immunoprecipitation and immunoblotting. Immunofluorescence was used to identify the specific cells that underwent apoptosis or necroptosis. The results showed that TNF-α induced apoptosis of astrocytes through the RIP1/FADD/Caspase-8 axis and induced necroptosis of neurons by the RIP3/MLKL signalling pathway. In addition, in vitro assay revealed that TNF-α secretion by microglia increased upon LSA stimulation and caused necroptosis of neurons. The present study provided the first evidence that TNF-α was secreted by microglia stimulated by AC infection, which caused cell death via parallel pathways of astrocyte apoptosis (mediated by the RIP1/FADD/caspase-8 axis) and neuron necroptosis (driven by the RIP3/MLKL complex). Our research comprehensively elucidated the mechanism of cell death after AC infection and provided new insight into targeting TNF-α signalling as a therapeutic strategy for CNS injury.Keywords
Funding Information
- Major Science and Technology Program of Hainan Province (ZDKJ202003)
- National Natural Science Foundation of China (81572023, 81371836)
- Guangdong Natural Science Foundation (2019A1515011541)
- Science and Technology Planning Project of Guangdong Province (2019B030316025)
- National Parasitic Resources Center of China (NPRC-2019-194-30)
- National Key Research and Development Program of China (2016YFC1202000, 2016YFC1200500)
- Open Foundation of Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University (2020TTM007)
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