DJ-1 exerts anti-inflammatory effects and regulates NLRX1-TRAF6 via SHP-1 in stroke

• Published in: Journal of neuroinflammation Vol. 17; no. 1; p. 81
• Main Authors: Peng, Li, Zhou, Yang, Jiang, Ning, Wang, Tingting, Zhu, Jin, Chen, Yanlin, Li, Linyu, Zhang, Jinyan, Yu, Shanshan, Zhao, Yong
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 09.03.2020; BioMed Central; BMC
• Subjects: Animals; Astrocyte; Astrocytes - metabolism; Care and treatment; Carrier proteins; Cytokines; Development and progression; DJ-1; Genetic aspects; Glucose; Health aspects; I/R injury; Immune response; Inflammation; Inflammation - metabolism; Ischemia; Male; Mitochondrial Proteins - metabolism; NLRX1-TRAF6; PARK7 protein; Protein Deglycase DJ-1 - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism; Rats; Rats, Sprague-Dawley; Reperfusion injury; Reperfusion Injury - metabolism; SHP-1; SHP-1 protein; Signal Transduction - physiology; Stroke - metabolism; TNF Receptor-Associated Factor 6 - metabolism; TRAF6 protein; Tumor necrosis factor-TNF; China; Beijing China; United States > US; DJ-1; Inflammation; NLRX1-TRAF6; Astrocyte; SHP-1; I/R injury
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-020-01764-x

Acute inflammation induced by reactive astrocytes after cerebral ischemia/reperfusion (I/R) injury is important for protecting the resultant lesion. Our previous study demonstrated that DJ-1 is abundantly expressed in reactive astrocytes after cerebral I/R injury. Here, we show that DJ-1 negatively regulates the inflammatory response by facilitating the interaction between SHP-1 and TRAF6, thereby inducing the dissociation of NLRX1 from TRAF6. We used oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro in primary astrocyte cultures and transient middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo to mimic I/R insult. The inhibition of DJ-1 expression increased the expression of the inflammatory cytokines TNF-α, IL-1β, and IL-6. DJ-1 knockdown facilitated the interaction between NLRX1 and TRAF6. However, the loss of DJ-1 attenuated the interaction between SHP-1 and TRAF6. In subsequent experiments, a SHP-1 inhibitor altered the interaction between SHP-1 and TRAF6 and facilitated the interaction between NLRX1 and TRAF6 in DJ-1-overexpressing astrocytes. These findings suggest that DJ-1 exerts an SHP-1-dependent anti-inflammatory effect and induces the dissociation of NLRX1 from TRAF6 during cerebral I/R injury. Thus, DJ-1 may be an efficacious therapeutic target for the treatment of I/R injury.