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TNF-α and α-synuclein fibrils differently regulate human astrocyte immune reactivity and impair mitochondrial respiration

Abstract : Here, we examine the cellular changes triggered by tumor necrosis factor alpha (TNF-a) and different alphasynuclein (aSYN) species in astrocytes derived from induced pluripotent stem cells. Human astrocytes treated with TNF-a display a strong reactive pro-inflammatory phenotype with upregulation of pro-inflammatory gene networks, activation of the nuclear factor kB (NF-kB) pathway, and release of pro-inflammatory cytokines, whereas those treated with high-molecular-weight aSYN fibrils acquire a reactive antigen (cross)-presenting phenotype with upregulation of major histocompatibility complex (MHC) genes and increased human leukocyte antigen (HLA) molecules at the cell surface. Surprisingly, the cell surface location of MHC proteins is abrogated by larger F110 fibrillar polymorphs, despite the upregulation of MHC genes. Interestingly, TNF-a and aSYN fibrils compete to drive the astrocyte immune reactive response. The astrocyte immune responses are accompanied by an impaired mitochondrial respiration, which is exacerbated in Parkinson’s disease (PD) astrocytes. Our data provide evidence for astrocytic involvement in PD pathogenesis and reveal their complex immune reactive responses to exogenous stressors.
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https://hal-cea.archives-ouvertes.fr/cea-03186002
Contributor : Ronald Melki <>
Submitted on : Tuesday, March 30, 2021 - 6:10:32 PM
Last modification on : Friday, April 2, 2021 - 3:30:17 AM

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Kaspar Russ, Gabriel Teku, Luc Bousset, Virginie Redeker, Sara Piel, et al.. TNF-α and α-synuclein fibrils differently regulate human astrocyte immune reactivity and impair mitochondrial respiration. Cell Reports, Elsevier Inc, 2021, 34 (12), pp.108895. ⟨10.1016/j.celrep.2021.108895⟩. ⟨cea-03186002⟩

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