NADPH oxidase-derived H2O2 mediates the regulatory effects of microglia on astrogliosis in experimental models of Parkinson's disease

Abstract

Astrogliosis has long been recognized in Parkinson's disease (PD), the most common neurodegenerative movement disorder. However, the mechanisms of how astroglia become activated remain unclear. Reciprocal interactions between microglia and astroglia play a pivotal role in regulating the activities of astroglia. The purpose of this study is to investigate the mechanism by which microglia regulate astrogliosis by using lipopolysaccharide (LPS) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse PD models. We found that the activation of microglia preceded astroglia in the substantia nigra of mice treated with either LPS or MPTP. Furthermore, suppression of microglial activation by pharmacological inhibition or genetic deletion of NADPH oxidase (NOX2) in mice attenuated astrogliosis. The important role of NOX2 in microglial regulation of astrogliosis was further mirrored in a mixed-glia culture system. Mechanistically, H2O2, a product of microglial NOX2 activation, serves as a direct signal to regulate astrogliosis. Astrogliosis was induced by H2O2 through a process in which extracellularly generated H2O2 diffused into the cytoplasm and subsequently stimulated activation of transcription factors, STAT1 and STAT3. STAT1/3 activation regulated the immunological functions of H2O2-induced astrogliosis since AG490, an inhibitor of STAT1/3, attenuated the gene expressions of both proinflammatory and neurotrophic factors in H2O2-treated astrocyte. Our findings indicate that microglial NOX2-generated H2O2 is able to regulate the immunological functions of astroglia via a STAT1/3-dependent manner, providing additional evidence for the immune pathogenesis and therapeutic studies of PD.

Manganese‐ and 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity display differences in morphological, electrophysiological and genome‐wide alterations: implications for idiopathic Parkinson's disease

“…STAT1/3, modulate glia‐mediated inflammatory responses in experimental PD (Hou et al . ). Inhibition of the JAK/STAT pathway protected against α‐synuclein‐mediated neuroinflammation and the resultant dopaminergic degeneration (Qin et al .…”

Subcellular expression of aquaporin-4 in substantia nigra of normal and MPTP-treated mice

“…Astrogliosis follows a similar time course; starting at day1 and increasing till day 7 after MPTP, when it reaches a plateau where the number of reactive astrocytes is more or less stable for one month (Hou et al 2017).…”

Acute Neuroinflammatory Response in the Substantia Nigra Pars Compacta of Rats after a Local Injection of Lipopolysaccharide

“…Microglial cells are resident macrophages of the CNS [ 67 ] and also bear TLR4, which can be activated by LPS to initiate an immune response entailing a wide range of immunomodulatory molecules such as proinflammatory cytokine and reactive oxygen species [ 68 ]. Since astrocytes are unresponsive to LPS [ 69 ], their activation depends on microglial NOX2-generated H 2 O 2 that subsequently stimulates activation of transcription factors STAT1 and STAT3 [ 70 ]. This evidence indicates that microglial activation precedes astrocyte activation as supported by our results.…”