Thioredoxin-1 induces immune tolerance against α-syn presented by MHC-II in microglia via promoting Tregs differentiation in MPTP-induced Parkinson’s disease mice

Parkinson's disease (PD) is a common neurodegenerative disease characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) and the formation of Lewy bodies composed of misfolded alpha-synuclein (α-syn). A growing number of studies indicate that microglia-mediated neuroinflammation and autoimmune responses are important pathological features of PD. Thioredoxin-1 (Trx-1), a multifunctional redox-regulatory protein, exerts neuroprotective effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD models, but its impact on microglia-mediated autoimmune responses in PD remains unexplored. In the present study, we demonstrated that Trx-1 suppressed microglial accumulation and the increase of pro-inflammatory cytokines. Furthermore, Trx-1 suppressed the increase of α-syn and major histocompatibility complex class II (MHC-II)-mediated antigen presentation in microglia induced by MPTP. Additionally, MPTP promoted T helper 17 (Th17) cell differentiation, inhibited forkhead box P3 (FOXP3) protein level and regulatory T (Treg) cell differentiation, and enhanced forkhead box O1 (FOXO1) phosphorylation and nuclear exclusion in the SNpc. All these pathological alterations induced by MPTP were effectively restored by Trx-1 overexpression. Our findings highlight the pivotal role of Trx-1 in microglia-mediated autoimmune responses, thereby providing a potential therapeutic target for PD.