AKR1B10, One of the Triggers of Cytokine Storm in SARS-CoV2 Severe Acute Respiratory Syndrome.

Clovis Chabert,Florent Chuffart,Pascal Poignard,Jean-Louis Pepin,Saadi Khochbin,Jean-Benoit Martinot,Candice Trocme,Domenico Iuso,Anne-Laure Vitte,Benjamin Lardinois,Sophie Rousseaux,Marlyse Buisson,Régis Debois

doi:10.3390/ijms23031911

Abstract

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 (TNFα), 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.

Highlights

The Coronavirus Disease 2019 (COVID-19) infection, which rapidly spread worldwide, was declared a pandemic on 11 March 2020 by the World Health Organisation [1]
Aldo-Keto Reductase 1B10 (AKR1B10) Is Overexpressed in the Lung of Deceased COVID-19 Patients and Correlated with an Enrichment of Pro-Inflammatory and Cytokine Genes
Over expression of AKR1B10GFP [1 μg] in H1299 lung cancer cells (Figure 3B) induces similar effects but with a lower order of magnitude for IL-6 and IL-1β than those observed in macrophages, and no significant modification of Tumour Necrosis Factor α (TNFα) expression (1.1-fold change from control, ns). These results suggest a key role for AKR1B10 in the pro-inflammatory cytokines production, which could make this factor an interesting therapeutic target to prevent or reduce the cytokine storm observed in a COVID-19 context

Summary

Introduction

The Coronavirus Disease 2019 (COVID-19) infection, which rapidly spread worldwide, was declared a pandemic on 11 March 2020 by the World Health Organisation [1]. The vaccination appears insufficient to completely prevent the circulation of the virus, and the occurrence of severe forms requiring the Intensive Care Unit (ICU) is still associated with high mortality rates [3]. Developing new approaches to detect SARS-CoV2 infection [4,5] and preventing the occurrence of the most severe cases of Acute Respiratory Distress Syndrome (ARDS) associated with severe COVID-19 forms represents a crucial strategy to reduce the burden of the COVID-19 pandemic. Long term use of corticosteroids during Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV2) infection may be deleterious [13]. For all these reasons, dissecting the mechanisms triggering the cytokine storm and identifying new pharmacological targets remains a burning question in COVID-19 management

Methods

Results

Conclusion