Preventing the cytokine storm observed in COVID-19 is a crucial goal for reducing the occurrence of severe acute respiratory failure and improving outcomes. Here, we identify Aldo-Keto Reductase 1B10 (AKR1B10) as a key enzyme involved in the expression of pro-inflammatory cytokines. The analysis of transcriptomic data from lung samples of patients who died from COVID-19 demonstrates an increased expression of the gene encoding AKR1B10. Measurements of the AKR1B10 protein in sera from hospitalised COVID-19 patients suggests a significant link between AKR1B10 levels and the severity of the disease. In macrophages and lung cells, the over-expression of AKR1B10 induces the expression of the pro-inflammatory cytokines Interleukin-6 ( IL-6) , Interleukin-1β ( IL-1β ) and Tumor Necrosis Factor a ( TNF α ), supporting the biological plausibility of an AKR1B10 involvement in the COVID-19-related cytokine storm. When macrophages were stressed by lipopolysaccharides (LPS) exposure and treated by Zopolrestat, an AKR1B10 inhibitor, the LPS-induced production of IL-6 , IL-1β , and TNFα is significantly reduced, reinforcing the hypothesis that the pro-inflammatory expression of cytokines is AKR1B10-dependant. Finally, we also show that AKR1B10 can be secreted and transferred via extracellular vesicles between different cell types, suggesting that this protein may also contribute to the multi-organ systemic impact of COVID-19. These experiments highlight a relationship between AKR1B10 production and severe forms of COVID-19. Our data indicate that AKR1B10 participates in the activation of cytokines production and suggest that modulation of AKR1B10 activity might be an actionable pharmacological target in COVID-19 management.
【저자키워드】 COVID-19, Inflammation, Cytokines, drug treatment, 【초록키워드】 Macrophage, Tumor, Cytokine storm, Cytokines, Respiratory failure, macrophages, IL-6, severity, interleukin-6, lung, Acute respiratory failure, Extracellular vesicles, cytokine, outcomes, Protein, interleukin, tumor necrosis factor, sera, management, Patient, pro-inflammatory cytokines, transcriptomic data, extracellular vesicle, experiment, inhibitor, expression, interleukin-1β, LPS, IL-1β, Hypothesis, Analysis, cell types, lipopolysaccharides, tumor necrosis, Activation, Factor, increased expression, modulation, enzyme, hospitalised COVID-19 patients, systemic impact, TNFα, pro-inflammatory cytokine, severe forms of COVID-19, over-expression, lung cells, gene encoding, pharmacological target, pro-inflammatory, AKR1B10, biological plausibility, TNF α, measurement, highlight, Occurrence, identify, died, significantly, involved, the disease, form, reduced, treated, contribute, reducing, induce, hospitalised COVID-19 patient, Preventing, Reductase, secreted, the cytokine storm, transferred, 【제목키워드】 SARS-CoV2, respiratory, Trigger, storm,