AIM2 controls microglial inflammation to prevent experimental autoimmune encephalomyelitis

• Published in: The Journal of experimental medicine Vol. 218; no. 5
• Main Authors: Ma, Chunmei, Li, Sheng, Hu, Yingchao, Ma, Yan, Wu, Yuqing, Wu, Chunyan, Liu, Xue, Wang, Bingwei, Hu, Gang, Zhou, Jiawei, Yang, Shuo
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 03-05-2021
• Subjects: Animals; Animals, Newborn; Cells, Cultured; Central Nervous System - immunology; Central Nervous System - metabolism; Central Nervous System - pathology; DNA-Activated Protein Kinase - genetics; DNA-Activated Protein Kinase - immunology; DNA-Activated Protein Kinase - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; DNA-Binding Proteins - metabolism; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Female; Gene Expression - immunology; Inflammasomes - genetics; Inflammasomes - immunology; Inflammasomes - metabolism; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Innate Immunity and Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microglia - immunology; Microglia - metabolism; Microglia - pathology; Neuroinflammation; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - immunology; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - genetics; Signal Transduction - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20201796

The role of the PYHIN family member absent in melanoma 2 (AIM2), another important inflammasome sensor, in EAE remains unclear. In this study, we found that AIM2 negatively regulates the pathogenesis of EAE independent of inflammasome activation. AIM2 deficiency enhanced microglia activation and infiltration of peripheral immune cells into the CNS, thereby promoting neuroinflammation and demyelination during EAE. Mechanistically, AIM2 negatively regulates the DNA-PK-AKT3 in microglia to control neuroinflammation synergistically induced by cGAS and DNA-PK. Administration of a DNA-PK inhibitor reduced the severity of the EAE. Collectively, these findings identify a new role for AIM2 in controlling the onset of EAE. Furthermore, delineation of the underlying inflammasome-independent mechanism highlights cGAS and DNA-PK signaling as potential targets for the treatment of heterogeneous MS.