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.
Domains
Life Sciences [q-bio]
Origin : Publisher files allowed on an open archive