Microglial AIM2 alleviates antiviral‐related neuro‐inflammation in mouse models of Parkinson's disease

• Published in: Glia 2022-12, Vol.70 (12), p.2409-2425
• Main Authors: Rui, Wen‐Juan, Li, Sheng, Yang, Lin, Liu, Ying, Fan, Yi, Hu, Ying‐Chao, Ma, Chun‐Mei, Wang, Bing‐Wei, Shi, Jing‐Ping
• Format: Article
• Language: English
• Subjects: AIM2; AKT protein; Animal models; antiviral; Bone marrow; Gene sequencing; Inflammasomes; Inflammation; Interferon; Interferon regulatory factor; Interferon regulatory factor 3; Melanoma; microglia; Movement disorders; MPTP; Neurodegenerative diseases; Neurological diseases; Parkinson's disease; Phosphorylation; Rodents; Therapeutic targets; Transfection; Transgenic mice
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.24260

Inflammasome involvement in Parkinson's disease (PD) has been intensively investigated. Absent in melanoma 2 (AIM2) is an essential inflammasome protein known to contribute to the development of several neurological diseases. However, a specific role for AIM2 in PD has not been reported. In this study, we investigated the effect of AIM2 in the N‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP)‐induced PD model by use of various knockout and bone marrow chimeric mice. The mechanism of action for AIM2 in PD was assessed by RNA‐sequencing and in vitro primary microglial transfection. Results were validated in the A30P transgenic mouse model of PD. In the MPTP mouse model, AIM2 activation was found to negatively regulate neuro‐inflammation independent of the inflammasome. Microglial AIM2 deficiency exacerbated behavioral and pathological features of both MPTP‐induced and transgenic PD mouse models. Mechanistically, AIM2 reduced cyclic GMP–AMP synthase (cGAS)‐mediated antiviral‐related inflammation by inhibition of AKT‐interferon regulatory factor 3 (IRF3) phosphorylation. These results demonstrate microglial AIM2 to inhibit the antiviral‐related neuro‐inflammation associated with PD and provide for a foundation upon which to identify new therapeutic targets for treatment of the disease. Main Points AIM2 plays an important role in mouse models of Parkinson's disease, independent of the inflammasome. Microglial AIM2 inhibits Parkinson's disease neuro‐inflammation and pathology. AIM2 inhibits AKT‐IRF3 phosphorylation, thereby alleviating cGAS‐mediated antiviral inflammation.