Aberrant microglial activation is a prominent feature of
neuroinflammation, which is implicated in the pathogenesis of
neurological disorders.
Fc receptor common γ-chain (FcRγ), one of the two immunoreceptor tyrosine-based activation motif-bearing adaptor
proteins, is abundantly expressed in microglia. It couples with different receptors, such as receptors for the Fc portion of
IgG. In this study, we observed increased FcRγ expression along with increased
IgG-binding during acute
neuroinflammation triggered by
MPTP intoxication, where adaptive immune responses should not be involved. Notably, FcRγ was expressed not only in the cell membrane but also in the cytoplasm in the activated microglia. FcRγ deficiency exacerbated microglial activation, pro-inflammatory factor upregulation, nigral dopaminergic neuronal loss and motor deficits, implicating a beneficial role of FcRγ in this model. Blockade of Fcγ receptor
ligation by
IgG in mice by
Endoglycosidase S treatment, a bacterial endo-β-N-
acetylglucosaminidase cleaving specifically the Asn297-linked
glycan of
IgG, or by using the mice deficient in mature B cells (muMT) with
IgG production defects, did not show similar phenotypes to those observed in FcRγ-deficient mice, indicating that the beneficial effect mediated by FcRγ did not depend on FcγR
ligation by
IgG. Further, FcRγ knockout aggravated the expression and activation of STAT1 in microglia, suggesting FcRγ modulated
neuroinflammation by dampening STAT1 signaling. Collectively, these results revealed that FcRγ-associated receptors could function as negative regulators of
neuroinflammation and dopaminergic neurodegeneration.