Innate immunity and inflammation (2)
Neuroinflammation (2)
Journal of Experimental Medicine (2)
Gang Hu
No Daily Weekly
AIM2 controls microglial inflammation to prevent experimental autoimmune encephalomyelitis
In Special Collection:
Innate Immune Signaling in Disease and Homeostasis
Chunmei Ma, Sheng Li, Yingchao Hu, Yan Ma, Yuqing Wu, Chunyan Wu, Xue Liu, Bingwei Wang, Gang Hu, Jiawei Zhou, Shuo Yang
Journal: Journal of Experimental Medicine
J Exp Med (2021) 218 (5): e20201796.
DOI: https://doi.org/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.
Gasdermin D in peripheral myeloid cells drives neuroinflammation in experimental autoimmune encephalomyelitis
Inflammation: from mechanism to disease
Sheng Li, Yuqing Wu, Dongxue Yang, Chunyan Wu, Chunmei Ma, Xue Liu, Paul N. Moynagh, Bingwei Wang, Gang Hu, Shuo Yang
J Exp Med (2019) 216 (11): 2562–2581.
The NLRP3 inflammasome is critical for EAE pathogenesis; however, the role of gasdermin D (GSDMD), a newly identified pyroptosis executioner downstream of NLRP3 inflammasome, in EAE has not been well defined. Here, we observed that the levels of GSDMD protein were greatly enhanced in the CNS of EAE mice, especially near the areas surrounding blood vessels. GSDMD was required for the pathogenesis of EAE, and GSDMD deficiency in peripheral myeloid cells impaired the infiltration of immune cells into the CNS, leading to the suppression of neuroinflammation and demyelination. Furthermore, the loss of GSDMD reduced the activation and differentiation of T cell in the secondary lymphoid organs and prevented T cell infiltration into CNS of EAE. The administration of inflammasome-related cytokines partially rescued the impairment of pathogenesis of EAE in GSDMD KO mice. Collectively, these findings provide the first demonstration of GSDMD in peripheral myeloid cells driving neuroinflammation during EAE pathogenesis.