LTB4-Driven Inflammation and Increased Expression of <i>ALOX5</i>/<i>ACE2</i> During Severe COVID-19 in Individuals With Diabetes

Abstract

Diabetes is a known risk factor for severe coronavirus disease 2019 (COVID-19), the disease caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is a lack of knowledge about the mechanisms involved in the evolution of COVID-19 in individuals with diabetes. We aimed to evaluate whether the chronic low-grade inflammation of diabetes could play a role in the development of severe COVID-19. We collected clinical data and blood samples of patients with and without diabetes hospitalized for COVID-19. Plasma samples were used to measure inflammatory mediators and peripheral blood mononuclear cells, for gene expression analysis of the SARS-CoV-2 main receptor system (<i>ACE2</i>/<i>TMPRSS2</i>), and for the main molecule of the leukotriene B₄ (LTB₄) pathway (<i>ALOX5</i>). We found that diabetes activates the LTB₄ pathway and that during COVID-19 it increases <i>ACE2</i>/<i>TMPRSS2</i> as well as <i>ALOX5</i> expression. Diabetes was also associated with COVID-19-related disorders, such as reduced oxygen saturation as measured by pulse oximetry/fraction of inspired oxygen (FiO₂) and arterial partial pressure of oxygen/FiO₂ levels, and increased disease duration. In addition, the expressions of <i>ACE2</i> and <i>ALOX5</i> are positively correlated, with increased expression in patients with diabetes and COVID-19 requiring intensive care assistance. We confirmed these molecular results at the protein level, where plasma LTB₄ is significantly increased in individuals with diabetes. In addition, IL-6 serum levels are increased only in individuals with diabetes requiring intensive care assistance. Together, these results indicate that LTB₄ and IL-6 systemic levels, as well as <i>ACE2</i>/<i>ALOX5</i> blood expression, could be early markers of severe COVID-19 in individuals with diabetes.