The Role And Mechanism Of Interleukin-19 In Chronic Cerebral Hypoperfusion Injury

Aim:Chronic cerebral hypoperfusion（CCH）is a chronic state of reduced cerebral perfusion blood flow,resulting cerebral ischemia and hypoxia and metabolic imbalance.Because of the sensitivity to ischemia and hypoxia,the white matter is vulnerable to irreversible damage during CCH,which is associated with Alzheimer’s disease and vascular cognitive impairment.Recent studies have shown that neuroinflammation plays an important role in white matter lesions,neuronal damage.Other studies have shown that IL-19 is an important cytokine regulating inflammatory response,but its expression and role in CCH related diseases remain unclear.Therefore,this study intends to explore the characteristics and mechanism of IL-19 in CCH.Methods:1.Serum samples of patients with vascular cognitive impairment were collected to detect the expression of IL-19 protein,and the expression was analyzed in combination with the score of Fazekas.2.Western blot,immunohistochemistry and immunofluorescence were used to detect the expression and distribution of IL-19 in CCH.3.The mouse models of wild type and IL-19^-/-with low perfusion were prepared at the same time,and the function of IL-19 in the course of CCH was further explored by using behavioral,PCR,immunohistochemical and other experimental methods.Results:1.The detection of 50 specimens meeting the inclusion criteria showed that the expression of IL-19 in the serum of patients with vascular dementia was up-regulated compared with the normal group（P<0.05）,there was positive correlation between the expression level of IL-19 and the score of Fazekas.2.Western blot results showed that the expression of IL-19 protein was up-regulated in the white matter of mice in the wild type CCH group compared with the sham operation group at four time points of one week,one month,two months and three months（P<0.001）.3.The Morris water maze test showed that compared with the sham operation group,the escape latency of the CCH group was prolonged and the number of platform crossings was reduced（P<0.05）,suggesting that the spatial memory ability of mice in the low-perfusion group was impaired.Compared with the wild type CCH group,the escape latency of the IL-19-/-CCH group was shortened and the number of platform crossings was increased,improving the spatial memory ability（P<0.05）.4.Luxol Fast Blue staining results and Western blotting results showed that compared with WT-type CCH group,the expression of GST3,MAG,MBP in the white matter of IL-19-/-CCH group was increased,the pathological injury of white matter structure was reduced.5.Immunofluorescence and immunohistochemical staining results showed that IL-19 was expressed in astrocytes.Compared with WT-type CCH group,the activation of microglia and astrocytes in IL-19^-/-CCH group was significantly reduced（P<0.05）,and the neuronal cell damage in IL-19^-/-CCH group was reduced（P<0.05）.Conclusions:1.IL-19 is involved in the pathophysiological process of CCH,and it is correlated with the degree of white matter damage.2.IL-19^-/-alleviates white matter injury by alleviating white matter demyelination and weakening glial cell activation,and plays a neuroprotective role in CCH.IL-19^-/-improves the spatial memory ability in the CCH mice.