cGAS and DDX41-STING mediated intrinsic immunity spreads intercellularly to promote neuroinflammation in SOD1 ALS model

Hong Yien Tan; Yean Kong Yong; Yuan Chao Xue; Huitao Liu; Tomomi Furihata; Esaki Muthu Shankar; Chen Seng Ng

doi:10.1016/j.isci.2022.104404

cGAS and DDX41-STING mediated intrinsic immunity spreads intercellularly to promote neuroinflammation in SOD1 ALS model

iScience. 2022 May 13;25(6):104404. doi: 10.1016/j.isci.2022.104404. eCollection 2022 Jun 17.

Authors

Hong Yien Tan^{1

2}, Yean Kong Yong¹, Yuan Chao Xue^{3

4

5}, Huitao Liu^{3

5}, Tomomi Furihata⁶, Esaki Muthu Shankar⁷, Chen Seng Ng⁸

Affiliations

¹ Laboratory Centre, Xiamen University Malaysia, Sepang, Selangor, Malaysia.
² School of Traditional Chinese Medicine, Xiamen University Malaysia, Sepang, Selangor, Malaysia.
³ Centre for Heart Lung Innovation, St Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
⁴ Department of Pathology and Laboratory of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
⁵ Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
⁶ Laboratory of Clinical Pharmacy and Experimental Therapeutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
⁷ Infection Biology, Department of Life Sciences, Central University of Tamil Nadu, Thiruvarur, India.
⁸ China-ASEAN College of Marine Sciences, Xiamen University Malaysia, Sepang, Selangor, Malaysia.

Abstract

Neuroinflammation exacerbates the progression of SOD1-driven amyotrophic lateral sclerosis (ALS), although the underlying mechanisms remain largely unknown. Herein, we demonstrate that misfolded SOD1 (SOD1^Mut)-causing ALS results in mitochondrial damage, thus triggering the release of mtDNA and an RNA:DNA hybrid into the cytosol in an mPTP-independent manner to activate IRF3- and IFNAR-dependent type I interferon (IFN-I) and interferon-stimulating genes. The neuronal hyper-IFN-I and pro-inflammatory responses triggered in ALS-SOD1^Mut were sufficiently robust to cause a strong physiological outcome in vitro and in vivo. cGAS/DDX41-STING-signaling is amplified in bystander cells through inter-neuronal gap junctions. Our results highlight the importance of a common DNA-sensing pathway between SOD1 and TDP-43 in influencing the progression of ALS.

Keywords: Immunology; Neuroscience; Pathophysiology.