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

Abstract

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 (<i>ACE2/TMPRSS2</i>) and main molecule of LTB<sub>4</sub> pathway (<i>ALOX5</i>). We found that diabetes activates LTB<sub>4</sub> pathway, and during COVID-19, it increases <i>ACE2/TMPRSS2</i> as well as <i>ALOX5</i> 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 <i>ACE2</i> and <i>ALOX5</i> 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 LTB<sub>4</sub> 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 LTB<sub>4</sub> 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.

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“…Notably, pro-inflammatory status, attenuation of innate immune response, possibly increased level of ACE2 in people with diabetes probably contribute to a worsening prognosis by SARS-CoV-2 and assistance for severe outcomes (Bonyek-- Silva et al, 2021).…”

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“…The hyperactivation of TLR4 might facilitate the production of proinflammatory cytokines which mainly contributes to the severity of COVID-19 [30]. Meanwhile, ALOX5 regulates the production of the inflammatory marker of COX-2 and plays a role in the severity of COVID-19, especially in hyperglycemic patients [31]. Over-expression of CD38 was associated with the hyperactivation of the immune system resulting in immune exhaustion and uncontrolled release of inflammatory cytokines [32].…”