Brain-resident microglia predominate over infiltrating myeloid cells in activation, phagocytosis and interaction with T-lymphocytes in the MPTP mouse model of Parkinson disease

Parkinson disease (PD) is characterized by dopaminergic neurodegeneration in the substantia nigra (SN). Recent evidence suggests that innate and adaptive immune responses can influence dopaminergic cell death in animal models of PD. However, the precise role of mononuclear phagocytes, key players in damaged tissue clearance and cross-talk with cells of adaptive immune system, remains open in PD. Mononuclear phagocytes in the brain occur as brain-resident microglia and as brain-infiltrating myeloid cells. To elucidate their differential contribution in the uptake of dopaminergic cell debris and antigen presentation capacity, we labeled nigral dopaminergic neurons retrogradely with inert rhodamine-conjugated latex retrobeads before inducing their degeneration by subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. We used green fluorescent protein (GFP)-expressing bone marrow chimeric mice to differentiate brain-infiltrating from brain-resident myeloid cells. We found that half of both endogenous (GFP −) and exogenous (GFP +) microglia (Iba1 +) in the SN incorporated the tracer from degenerating dopaminergic neurons 1d after MPTP intoxication. In absolute numbers, endogenous microglia were much more activated to macrophages compared to exogenous myeloid cells at 1d after MPTP. Mainly the endogenous, tracer-phagocytosing microglia expressed the major histocompatibility complex (MHC) class II molecule for antigen presentation. Additionally, T-lymphocytes (Iba1 −/GFP +/CD3 +), which infiltrate the MPTP-lesioned SN, were mainly in direct contact with MHCII + endogenous microglia. Our data suggest that brain-resident microglia are predominantly implicated in the removal of dopaminergic cell debris and the cross-talk with infiltrating T-lymphocytes in the SN in the MPTP mouse model of PD.

► MPTP-induced dopaminergic cell death is accompanied primarily by resident microglial activation. ► Debris of degenerating dopaminergic cells are predominantly phagocytosed by resident microglia. ► CD25 + T-lymphocytes contact resident MHCII + phagocytes in the MPTP-lesioned substantia nigra.