LTB4-Driven Inflammation and Increased Expression of ALOX5/ACE2 During Severe COVID-19 in Individuals with Diabetes

Diabetes is a known risk factor for severe COVID-19, the disease caused by the new coronavirus SARS-CoV-2. However, there is a lack of knowledge about the mechanisms involved in the evolution of COVID-19 in individuals with diabetes. Therefore, 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 hospitalized patients for COVID-19, with diabetes and without diabetes. Plasma samples were used to measure inflammatory mediators and peripheral blood mononuclear cells, for gene expression analysis of SARS-CoV-2 main receptor system (ACE2/TMPRSS2) and main molecule of LTB₄ pathway (ALOX5). We found that diabetes activates LTB₄ pathway, and during COVID-19, it increases ACE2/TMPRSS2 as well as ALOX5 expression. Diabetes was also associated with COVID-19-related disorders, such as reduced SpO2/FiO2 and PaO2/FiO2 levels, and increased disease duration. In addition, the expression of ACE2 and ALOX5 are positively correlated, with increased expression in COVID-19 patients with diabetes requiring intensive care assistance. We confirmed these molecular results at the protein level, where plasma LTB₄ is significantly increased in individuals with diabetes. Besides, 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, ACE2/ALOX5 blood expression could be early markers of severe COVID-19 in individuals with diabetes.