Abstract
The novel therapeutic target cytokine LIGHT (TNFSF14) was recently shown to play a major role in COVID-19-induced acute respiratory distress syndrome (ARDS). This study aims to investigate the associations of plasma LIGHT and another potentially targetable cytokine, interleukin-18 (IL-18), with ARDS, acute hypoxic respiratory failure (AHRF), or acute kidney injury (AKI), caused by non-COVID-19 viral or bacterial sepsis. A total of 280 subjects diagnosed with sepsis, including 91 cases with sepsis triggered by viral infections, were investigated in this cohort study. Day 0 plasma LIGHT and IL-18, as well as 59 other biomarkers (cytokines, chemokines, and acute-phase reactants) were measured by sensitive bead immunoassay and associated with symptom severity. We observed significantly increased LIGHT level in both bacterial sepsis patients (p = 1.80 × 10−5) and patients with sepsis from viral infections (p = 1.78 × 10−3). In bacterial sepsis, increased LIGHT level was associated with ARDS, AKI, and higher Apache III scores, findings also supported by correlations of LIGHT with other biomarkers of organ failure. IL-18 levels were highly variable across individuals and consistently correlated with Apache III scores, mortality, and AKI in both bacterial and viral sepsis. There was no correlation between LIGHT and IL-18. For the first time, we demonstrate independent effects of LIGHT and IL-18 in septic organ failure. The association of plasma LIGHT with AHRF suggests that targeting the pathway warrants exploration, and ongoing trials may soon elucidate whether this is beneficial. Given the large variance of plasma IL-18 among septic subjects, targeting this pathway requires precise application.
Highlights
Introduction iationsThe cytokine LIGHT (CD258), known as tumor necrosis factor superfamily member 14 (TNFSF14), is a secreted protein of the TNF superfamily, recognized by the herpesvirus entry mediator (HVEM, known as TNFRSF14), the lymphotoxin B receptor (LTβR, known as TNFRSF3), and decoy receptor DcR3 [1].LIGHT exhibits inducible expression and competes with herpes virus glycoprotein D for binding to HVEM on T lymphocytes [2]
A previous study showed that IL-18 mediates ischemic acute tubular necrosis in acute kidney injury (AKI) [37], whereas our study shows that IL-18BP has much stronger correlation with AKI than IL-18 in sepsis
The detrimental roles of LIGHT in multi-organ failure were mainly seen in bacterial sepsis, including acute respiratory distress syndrome (ARDS)/acute hypoxic respiratory failure (AHRF), AKI, and its association with higher
Summary
Introduction iationsThe cytokine LIGHT (CD258), known as tumor necrosis factor superfamily member 14 (TNFSF14), is a secreted protein of the TNF superfamily, recognized by the herpesvirus entry mediator (HVEM, known as TNFRSF14), the lymphotoxin B receptor (LTβR, known as TNFRSF3), and decoy receptor DcR3 ( known as TNFRSF6B) [1].LIGHT exhibits inducible expression and competes with herpes virus glycoprotein D for binding to HVEM on T lymphocytes [2]. LIGHT is a ligand for TNFRSF14, which is a member of the tumor necrosis factor receptor superfamily, known as HVEM ligand (HVEML). This protein functions as a costimulatory factor for the activation of lymphoid cells aimed at opposing infection by herpesvirus [2]. It stimulates the proliferation of T cells and triggers the apoptosis of various tumor cells [3]. In addition to LIGHT, interleukin-18 (IL-18) has been repeatedly highlighted as a major player in sepsis [4,5]
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