Association of plasma level of high-mobility group box-1 with necroptosis and sepsis outcomes

Hongseok Yoo,Yunjoo Im,Jin Young Lee,Ryoung-Eun Ko,Junseon Park,Kyeongman Jeon

doi:10.1038/s41598-021-88970-6

Hongseok Yoo, Yunjoo Im + Show 4 more

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https://doi.org/10.1038/s41598-021-88970-6

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Journal: Scientific Reports	Publication Date: May 4, 2021
Citations: 22	License type: open-access

Affiliation: Samsung Medical Center, Sungkyunkwan University

Abstract

The role of high-mobility group box-1 (HMGB1) in outcome prediction in sepsis is controversial. Furthermore, its association with necroptosis, a programmed cell necrosis mechanism, is still unclear. The purpose of this study is to identify the association between the plasma levels of HMGB1 and the severity and clinical outcomes of sepsis, and to examine the correlation between HMGB1 and key executors of necroptosis including receptor-interacting kinase 3 (RIPK3) and mixed lineage kinase domain-like- (MLKL) proteins. Plasma HMGB1, RIPK3, and MLKL levels were measured with the enzyme-linked immunosorbent assay from the derivation cohort of 188 prospectively enrolled, critically-ill patients between April 2014 and December 2016, and from the validation cohort of 77 patients with sepsis between January 2017 and January 2019. In the derivation cohort, the plasma HMGB1 levels of the control (n = 46, 24.5%), sepsis (n = 58, 30.9%), and septic shock (n = 84, 44.7%) groups were significantly increased (P < 0.001). A difference in mortality between high (≥ 5.9 ng/mL) and low (< 5.9 ng/mL) HMGB1 levels was observed up to 90 days (Log-rank test, P = 0.009). There were positive linear correlations of plasma HMGB1 with RIPK3 (R2 = 0.61, P < 0.001) and MLKL (R2 = 0.7890, P < 0.001). The difference in mortality and correlation of HMGB1 levels with RIPK3 and MLKL were confirmed in the validation cohort. Plasma levels of HMGB1 were associated with the severity and mortality attributed to sepsis. They were correlated with RIPK3 and MLKL, thus suggesting an association of HMGB1 with necroptosis.

Highlights

The role of high-mobility group box-1 (HMGB1) in outcome prediction in sepsis is controversial
Growing evidence indicates that among various mechanisms, HMGB1 leakage may be induced by the regulated cell death (RCD) mechanism of necroptosis, caspase-independent receptor-interacting protein kinase (RIPK), and mixed lineage kinase domain-like protein (MLKL)[13]
The number of patients who required vasopressor support, blood lactic acid levels, the number of septic shock patients, and severity of illness based on simplified acute physiology score 3 (SAPS 3), APACHE II, and sequential organ failure assessment (SOFA) scores, was higher in the case of the high-HMGB1 group

Summary

Introduction

The role of high-mobility group box-1 (HMGB1) in outcome prediction in sepsis is controversial. The purpose of this study is to identify the association between the plasma levels of HMGB1 and the severity and clinical outcomes of sepsis, and to examine the correlation between HMGB1 and key executors of necroptosis including receptor-interacting kinase 3 (RIPK3) and mixed lineage kinase domain-like- (MLKL) proteins. Plasma levels of HMGB1 were associated with the severity and mortality attributed to sepsis They were correlated with RIPK3 and MLKL, suggesting an association of HMGB1 with necroptosis. Abbreviations APACHE II Acute physiology, age, chronic health evaluation II DAMP Damage-associated molecular pattern HMGB1 High-mobility group box-1 ICU Intensive care unit MLKL Mixed lineage kinase domain-like protein RCD Regulated cell death RIPK3 Receptor-interacting protein kinase-3 SAPS3 Simplified acute physiology score 3 SOFA Sequential organ failure assessment. The plasma levels of HMGB1 were correlated to those of RIPK3 and MLKL to identify the relationship of HMGB1 with n ecroptosis[14,15]

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