Neural Regeneration Research ›› 2021, Vol. 16 ›› Issue (12): 2453-2464.doi: 10.4103/1673-5374.313049

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SOCS1/JAK2/STAT3 axis regulates early brain injury induced by subarachnoid hemorrhage via inflammatory responses

Yang Wang1, #, Xiang-Qian Kong2, 3, #, Fei Wu1, #, Bin Xu4, De-Jun Bao1, Chuan-Dong Cheng1, Xiang-Ping Wei1, Yong-Fei Dong1, *, Chao-Shi Niu1, 5, *   

  1. 1Department of Neurosurgery, First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, China; 2Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China; 3Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China; 4Anhui Medical College, Anhui Provincial Medical Genetics Center, Hefei, Anhui Province, China; 5Anhui Province Key Laboratory of Brain Function and Brain Disease, Hefei, Anhui Province, China
  • Online:2021-12-15 Published:2021-05-15
  • Contact: Yong-Fei Dong, MD, dyf.w@163.com; Chao-Shi Niu, PhD, ah_neurosurgery@163.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81500375 (to XQK); the Fundamental Research Funds for the Central Universities, No. WK9110000112 (to YW); the Anhui Provincial Natural Science Foundation of China, No. 1508085QH184 (to YW); and Shandong Provincial Natural Science Foundation of China, No. ZR2015HQ001 (to XQK).

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Abstract: The SOCS1/JAK2/STAT3 axis is strongly associated with tumor growth and progression, and participates in cytokine secretion in many diseases. However, the effects of the SOCS1/JAK2/STAT3 axis in experimental subarachnoid hemorrhage remain to be studied. A subarachnoid hemorrhage model was established in rats by infusing autologous blood into the optic chiasm pool. Some rats were first treated with JAK2/STAT3 small interfering RNA (Si-JAK2/Si-STAT3) or overexpression plasmids of JAK2/STAT3. In the brains of subarachnoid hemorrhage model rats, the expression levels of both JAK2 and STAT3 were upregulated and the expression of SOCS1 was downregulated, reaching a peak at 48 hours after injury. Simultaneously, the interactions between JAK2 and SOCS1 were reduced. In contrast, the interactions between JAK2 and STAT3 were markedly enhanced. Si-JAK2 and Si-STAT3 treatment alleviated cortical neuronal cell apoptosis and necrosis, destruction of the blood–brain barrier, brain edema, and cognitive functional impairment after subarachnoid hemorrhage. This was accompanied by decreased phosphorylation of JAK2 and STAT3 protein, decreased total levels of JAK2 and STAT3 protein, and increased SOCS1 protein expression. However, overexpression of JAK2 and STAT3 exerted opposite effects, aggravating subarachnoid hemorrhage-induced early brain injury. Si-JAK2 and Si-STAT3 inhibited M1-type microglial conversion and the release of pro-inflammatory factors (inducible nitric oxide synthase, interleukin-1β, and tumor necrosis factor-α) and increased the release of anti-inflammatory factors (arginase-1, interleukin-10, and interleukin-4). Furthermore, primary neurons stimulated with oxyhemoglobin were used to simulate subarachnoid hemorrhage in vitro, and the JAK2 inhibitor AG490 was used as an intervention. The in vitro results also suggested that neuronal protection is mediated by the inhibition of JAK2 and STAT3 expression. Together, our findings indicate that the SOCS1/JAK2/STAT3 axis contributes to early brain injury after subarachnoid hemorrhage both in vitro and in vivo by inducing inflammatory responses. This study was approved by the Animal Ethics Committee of Anhui Medical University and the First Affiliated Hospital of University of Science and Technology of China (approval No. LLSC-20180202) on March 1, 2018.

Key words: brain injury, cytokines, in vitro model, in vivo model, inflammation, microglia, SOCS1/JAK2/STAT3 axis, subarachnoid hemorrhage

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