Cystathionine β-Synthase Suppresses NLRP3 Inflammasome Activation via Redox Regulation in Microglia

Yu-Jie Mou; Ya-Ting Ma; Xin Yuan; Miao Wang; Yang Liu; Chong-Shuang Pei; Chun-Feng Liu; Xiao-Ou Hou; Li-Fang Hu

doi:10.1089/ars.2022.0174

Cystathionine β-Synthase Suppresses NLRP3 Inflammasome Activation via Redox Regulation in Microglia

Antioxid Redox Signal. 2023 Sep 5. doi: 10.1089/ars.2022.0174. Online ahead of print.

Authors

Yu-Jie Mou^{1

2}, Ya-Ting Ma^{1

3}, Xin Yuan³, Miao Wang^{1

3}, Yang Liu^{1

3}, Chong-Shuang Pei^{1

3}, Chun-Feng Liu^{1

3}, Xiao-Ou Hou^{1

3}, Li-Fang Hu^{1

3}

Affiliations

¹ Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China.
² Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
³ Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.

PMID: 37464816
DOI: 10.1089/ars.2022.0174

Abstract

Aims: Cystathionine β-synthase (CBS) is essential for homocysteine (Hcy) transsulfuration, yielding cysteine as a common precursor of hydrogen sulfide (H₂S), glutathione (GSH), and other sulfur molecules, which produce neuroprotective effects in neurological conditions. We previously reported a disruption of microglial CBS/H₂S signaling in a Parkinson's disease (PD) mouse model. Yet, it remains unclear whether CBS affects nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome activity and other pathologies in PD. Results: Microglial CBS expression decreased after lipopolysaccharide (LPS) stimulation. Elevated GSSG (the oxidized GSH) content and decreased H₂S generation were found in the brains of microglial cbs conditional-knockout (cbs^cKO) mice, whereas serum and brain Hcy levels remained unaltered. Moreover, microglial cbs^cKO mice were susceptible to NLRP3 inflammasome activation and dopaminergic neuron losses caused by LPS injection into the substantia nigra, whereas cbs overexpression or activation produced opposite effects. In vitro studies showed that cbs overexpression or activation suppressed microglial NLRP3 inflammasome activation and interleukin (IL)-1β secretion by reducing mitochondrial reactive oxygen species (mitoROS) level. Conversely, ablation of cbs enhanced NLRP3 expression and mitoROS generation and augmented microglial NLRP3 inflammasome activity in response to adenosine triphosphate challenge, which was blocked by the mitoROS scavenger. Innovation and Conclusion: The study demonstrated an elevated GSSG level and reduced H₂S generation, which correlated with a susceptible status of microglia in the brain of cbs^cKO mice. Our findings reveal a critical role of CBS in restraining the microglial NLRP3 inflammasome by controlling redox homeostasis and highlight that activation or upregulation of CBS may become a potential strategy for PD treatment.

Keywords: CBS; Parkinson's disease; hydrogen sulfide; inflammasome; microglia; redox homeostasis.