AUTHOR=Qu Yewei , Yang Fan , Meng Fanwei , Chen Xi , Zhang Qingqing , Yu Tian , Wen Shirong , Pan Yujun 

TITLE=Plasma Concentration of Tumor Necrosis Factor-Stimulated Gene-6 as a Novel Diagnostic and 3-Month Prognostic Indicator in Non-Cardioembolic Acute Ischemic Stroke

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.713379

DOI=10.3389/fimmu.2022.713379

ISSN=1664-3224

ABSTRACT=Background: Tumor Necrosis Factor-Stimulated Gene-6 (TSG-6) is a multi-functional, anti-inflammatory and protective protein, while the association between TSG-6 and acute ischemic stroke (AIS) remains unclear in humans. This study aims to investigate the potential diagnostic and short-term-prognosis predictive values of TSG-6 in non-cardioembolic AIS.
Methods: A total of 134 non-cardioembolic AIS patients within 24h after AIS onset and 40 control subjects were recruited. Using an AIS dataset from Gene Expression Omnibus database and setting the median expression level of TNFAIP6 as the cut-off point, data were divided into TNFAIP6-high and TNFAIP6-low expression groups. Differently expressed genes (DEGs) were extracted to perform gene enrichment analysis and protein-protein interaction (PPI) network. Baseline data were analyzed in a four-group comparison plotted as plasma TSG-6 concentration median and 25th/75th percentiles. The correlative factors of 3-month outcome were evaluated by logistic regression. TSG-6 concentrations and TSG-6-to-interleukin-8 ratios were compared in block design. A receiver-operating-characteristic curve was used to analyze the detective value of TSG-6 and 3-month-prognosis predictive values of TSG-6 and TSG-6-to-interleukin-8 ratio.  
Results: Non-cardioembolic AIS patients had significantly higher plasma TSG-6 levels than control subjects (P<0.0001). Large-artery-atherosclerosis group had significantly higher TSG-6 levels than small-artery-occlusion group (P=0.0184). 782 DEGs might be both AIS-related and TNFAIP6-correlated genes and 17 targets were deemed AIS-related with closely relevant to TNFAIP6. Interleukin-8 was selected for further study. National Institutes of Health Stroke Scale and Acute Stroke Registry and Analysis of Lausanne score at admission, lesion volume, neutrophil count, neutrophil-to-lymphocyte ratio, and interleukin-8 level were positively correlated with TSG-6 level respectively (P<0.0001). Unfavorable-outcome group had meaningfully higher TSG-6 levels (P<0.0001) and lower TSG-6-to-interleukin-8 ratios (P<0.0001) than favorable-outcome group. After adjusting for confounding variables, elevated TSG-6 levels remained independently associated with 3-month poor prognosis of non-cardioembolic AIS (P=0.017). In non-cardioembolic AIS, the cutoff values of TSG-6 concentration for detection and 3-month-prognosis prediction, and TSG-6-to-interleukin-8 ratio for 3-month-prognosis prediction were 8.13 ng/ml (AUC, 0.774[0.686-0.861]; P<0.0001), 10.21 ng/ml (AUC, 0.795[0.702-0.887]; P<0.0001) and 1.505 (AUC, 0.873[0.795-0.951]; P<0.0001) . 
Conclusions: Plasma TSG-6 concentration was a novel indicator for non-cardioembolic AIS diagnosis and 3-month prognosis. Elevated TSG-6-to-interleukin-8 ratio might suggest a 3-month favorable outcome.