1. Introduction
Since Parkinson’s disease (PD) has been shown to be not only a degenerative but also an inflammatory disease of the central nervous system, evidence of CD4+ T cell infiltration in the substantia nigra (SN) has been found in different PD animal models and PD patients(Baird et al. , 2019; Galiano-Landeira et al. , 2020; Subbarayan et al. , 2020). CD4+ T cells and a subset of them Th17 cells was shown to have deleterious roles in PD(Bolte and Lukens, 2018; Dutta et al. , 2019; Liu et al. , 2019). HMGB1 plays an important role in the differentiation of CD4+ T cells into Th17(Jhun et al. , 2015; Suet al. , 2011). Our previous study also confirmed that HMGB1 promotes the differentiation of CD4+ T cells to Th17 in a microglia-dependent manner in vitro (Tian et al. , 2020). Peripheral monocyte/macrophage infiltration in SN of PD model animals is correlated with the course of PD(Harms et al. , 2018; Pillny et al. , 2021; Santaella et al. , 2020; Xie et al. , 2017). However, the specific role of these infiltrating peripherally derived monocytes/macrophages is unclear.
HMGB1 is an evolutionarily highly conserved nuclear protein that can be actively secreted by immune cells during stress or passively released after cellular injury(Andersson et al. , 2018; Zimmermann et al. , 2004). According to the different redox forms of the three cysteine ​​sites of HMGB1, HMGB1 has a fully reduced form (frHMGB1), a disulfide bond form (dsHMGB1) and a fully oxidized form, with completely different biological functions (Tian et al. , 2021). The deleterious role of elevated HMGB1 in PD has been repeatedly demonstrated(Santoro et al. , 2016; Sasaki et al. , 2016). frHMGB1 has chemotactic roles, however, whether HMGB1 plays a role in PD and whether frHMGB1 elicits the involvement of peripheral immune cells in neuroinflammation in PD remains to be explored.
Our previous data showed that HMGB1 A Box, a competitive inhibitor of HMGB1, had a very significant inhibitory effect on T cell infiltration including Th17 in the SN and in MPP+-induced PD cells in vitro excluding the influence of peripheral immune cells. In the model, it was confirmed that the induction of Th17 by HMGB1 is dependent on microglia(Tian et al. , 2020). However, in this study, we found that microglia expressed significantly lower levels of MHC II than macrophages, it was reported that the presence monocyte/macrophage in the midbrain in an α-syn-induced mouse model(Choi et al. , 2020; Harms et al. , 2018; Tentillier et al. , 2016). Another study found an increase of HLA-DR expression on monocytes in cerebrospinal fluid and of CD45RO+ T cells in peripheral blood in PD patients(Fiszer et al. , 1994). The peripheral monocytes may also promote Th17 differentiation in PD.