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

  • J Neuroinflammation. 2020 Mar 9;17(1):81. doi: 10.1186/s12974-020-01764-x.
Li Peng  1  2  3  4 ,  Yang Zhou  1  2  3  4 ,  Ning Jiang  1  2  3  4 ,  Tingting Wang  1  2  3  4 ,  Jin Zhu  1  2  3  4 ,  Yanlin Chen  1  2  3  4 ,  Linyu Li  1  2  3  4 ,  Jinyan Zhang  1  2  3  4 ,  Shanshan Yu  5  6  7  8 ,  Yong Zhao  9  10  11  12
Affiliations
  • 1. Department of Pathology, Chongqing Medical University, Yixueyuan Road 1, Chongqing, 400016, People's Republic of China.
  • 2. Molecular Medical Laboratory, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
  • 3. Institute of Neuroscience, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
  • 4. Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
  • 5. Department of Pathology, Chongqing Medical University, Yixueyuan Road 1, Chongqing, 400016, People's Republic of China. [email protected].
  • 6. Molecular Medical Laboratory, Chongqing Medical University, Chongqing, 400016, People's Republic of China. [email protected].
  • 7. Institute of Neuroscience, Chongqing Medical University, Chongqing, 400016, People's Republic of China. [email protected].
  • 8. Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, 400016, People's Republic of China. [email protected].
  • 9. Department of Pathology, Chongqing Medical University, Yixueyuan Road 1, Chongqing, 400016, People's Republic of China. [email protected].
  • 10. Molecular Medical Laboratory, Chongqing Medical University, Chongqing, 400016, People's Republic of China. [email protected].
  • 11. Institute of Neuroscience, Chongqing Medical University, Chongqing, 400016, People's Republic of China. [email protected].
  • 12. Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, 400016, People's Republic of China. [email protected].
PMID: 32151250 DOI: 10.1186/s12974-020-01764-x
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords
Astrocyte; DJ-1; I/R injury; Inflammation; NLRX1-TRAF6; SHP-1.
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