The hidden role of NLRP3 inflammasome in obesity‐related COVID‐19 exacerbations: Lessons for drug repurposing

Abstract

COVID-19, the illness caused by SARS-CoV-2, has a wide-ranging clinical spectrum that, in the worst-case scenario, involves a rapid progression to severe acute respiratory syndrome and death. Epidemiological data show that obesity and diabetes are among the main risk factors associated with high morbidity and mortality. The increased susceptibility to SARS-CoV-2 infection documented in obesity-related metabolic derangements argues for initial defects in defence mechanisms, most likely due to an elevated systemic metabolic inflammation ("metaflammation"). The NLRP3 inflammasome is a master regulator of metaflammation and has a pivotal role in the pathophysiology of either obesity or diabetes. Here, we discuss the most recent findings suggesting contribution of NLRP3 inflammasome to the increase in complications in COVID-19 patients with diabesity. We also review current pharmacological strategies for COVID-19, focusing on treatments whose efficacy could be due, at least in part, to interference with the activation of the NLRP3 inflammasome.

COVID-19 Pathophysiology Predicts That Ischemic Stroke Occurrence Is an Expectation, Not an Exception—A Systematic Review

“…However, in patients with impaired immune responses, such as the elderly, there is an unprecedented activation of the NLRP3 inflammasome coupled with mitochondrial dysfunction and increased proportions of the mitochondrial reactive oxygen species, which further worsen tissue damage and initiate cell death ( 66 ). In patients with obesity and diabetes in which NLRP3 inflammasomes are already basally activated, and the immune responses are suboptimal, viral-induced activation of the former may worsen a preexisting chronic inflammatory state ( 67 ). Hence, this factor may be related to the poor outcomes of elderly patients with COVID-19 and stroke and with traditional cardiovascular risk factors such as obesity and diabetes ( 10 ).…”

Drug repurposing of dermatologic medications to treat coronavirus disease 2019: Science or fiction?

“…Their activation has been reported to play a role in the pathogenesis of several inflammatory and infectious diseases, including SARS-CoV and SARS-CoV-2 infections. 76 Upon metabolic activation, dapsone is competing covalently with proteins that activate the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing (NLRP3) inflammasome, the overactivation of which contributes to the pathogenesis of cardiometabolic disorders and plays a pivotal role in the pathophysiology of either obesity or diabetes. This, in turn, somewhat explains the idiosyncratic reactions characterizing dapsone hypersensitivity syndrome, a severe adverse reaction showing many clinical manifestations similar to those observed in severe COVID-19.…”

“…In addition, another viroporin 3a is found to induce NLRP3 inflammasome activation through unclear mechanisms, which is observed in COVID-19. 76 Colchicine counteracts the assembly of the NLRP3 inflammasome, thereby reducing the release of IL-1 b and an array of other ILs, including IL-6, that are formed in response to danger signals. 86…”

COVID‐19: A Case for Inhibiting NLRP3 Inflammasome, Suppression of Inflammation with Curcumin?

“…Recent studies emphasis on the key role of NLRP3 inflammasome in immunopathogenesis of severe COVID-19 especially in patients with increased risk (ex diabetes and obesity). [34][35][36] Curcumin activates nuclear factor erythroid 2-related factor 2 (NRF2). The Nrf2 is a transcription factor that increases the expression of a number of antioxidant proteins under stress.…”

“…Activation of the inflammasome is likely to be involved in the formation of severe cytokine storm, which subsequently causes ARDS and MODS and ultimately leads to death. Recent studies emphasis on the key role of NLRP3 inflammasome in immunopathogenesis of severe COVID‐19 especially in patients with increased risk (ex diabetes and obesity) 34‐36 . Curcumin activates nuclear factor erythroid 2‐related factor 2 (NRF2).…”