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.