HMGB1 A Box binds to CXCR4 to inhibit HMGB1/CXCL12 mediating macrophage
and T cell infiltration and prevents neuronal damage in Parkinson’s
Disease
Abstract
Background and purpose: Our previous work proved that HMGB1 A Box
significantly protected TH+ neurons in Parkinson’s disease (PD) model
mice and inhibited microglia activation and T cell infiltration
including Th17 in the substantia nigra (SN). This study explored the
mechanism of Th17 differentiation and how A Box inhibiting this process.
Experimental approach: Clodronate liposomes were used to deplete the
peripheral monocytes of mice, infused the labeled CD3+ T cells, and used
immunoprecipitation to knock down the primary cells HMGB1 in vitro. At
the same time, we combined the data of serum and blood cells of PD
patients to study. Key results: Depletion of peripheral
monocytes/macrophages reduced Th17 cell infiltration in the SN of MPTP
mice and protected TH+ neurons. Co-culture experiments with knockdown of
HMGB1 in primary cells showed that HMGB1, which induces
monocyte/macrophage migration and infiltration into the SN, originates
from neurons rather than glial cells. Data from MPP+-treated midbrain
cell models and assays associated with adoptive transfer of CD3+ cells
suggest that monocyte/macrophage and T cell migration into the SN is
mediated by HMGB1/CXCL12-CXCR4. Co-immunoprecipitation and
immunofluorescence confirmed that HMGB1 A Box bind to CXCR4 on T cells
and macrophages, thereby competitively inhibiting their infiltration in
SN. The HMGB1/CXCL12 complex is also present in the serum of PD
patients. Conclusions and implications: HMGB1 A Box protects TH+ neurons
by binding CXCR4 to inhibit the migration / infiltration of T cells and
macrophages to SN mediated by HMGB1 / CXCL12 complex formed by neuron
derived HMGB1.