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

• Published in: Diabetes (New York, N.Y.) Vol. 70; no. 9; pp. 2120 - 2130
• Main Authors: Bonyek-Silva, Icaro, Machado, Antônio Fernando Araújo, Cerqueira-Silva, Thiago, Nunes, Sara, Silva Cruz, Márcio Rivison, Silva, Jéssica, Santos, Reinan Lima, Barral, Aldina, Oliveira, Pablo Rafael Silveira, Khouri, Ricardo, Serezani, C. Henrique, Brodskyn, Cláudia, Caldas, Juliana Ribeiro, Barral-Netto, Manoel, Boaventura, Viviane, Tavares, Natalia Machado
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 01-09-2021
• Subjects: ACE2; Angiotensin-converting enzyme 2; Blood pressure; Complications; Coronaviruses; COVID-19; Diabetes; Diabetes mellitus; Gene expression; Inflammation; Intensive care; Interleukin 6; Leukocytes (mononuclear); Leukotriene B4; Oxygen; Patients; Peripheral blood mononuclear cells; Risk factors; Serum levels; Severe acute respiratory syndrome coronavirus 2
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db20-1260

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 (ACE2/TMPRSS2), and for the main molecule of the leukotriene B4 (LTB4) pathway (ALOX5). We found that diabetes activates the LTB4 pathway and that during COVID-19 it increases ACE2/TMPRSS2 as well as ALOX5 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 ACE2 and ALOX5 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 ACE2/ALOX5 blood expression, could be early markers of severe COVID-19 in individuals with diabetes.