NLRP3 Inflammasome: The Stormy Link Between Obesity and COVID-19

Abstract

Several countries around the world have faced an important obesity challenge for the past four decades as the result of an obesogenic environment. This disease has a multifactorial origin and it is associated with multiple comorbidities including type 2 diabetes, hypertension, osteoarthritis, metabolic syndrome, cancer, and dyslipidemia. With regard to dyslipidemia, hypertriglyceridemia is a well-known activator of the NLRP3 inflammasome, triggering adipokines and cytokines secretion which in addition induce a systemic inflammatory state that provides an adequate scenario for infections, particularly those mediated by viruses such as HIV, H1N1 influenza, and SARS-CoV-2. The SARS-CoV-2 infection causes the coronavirus disease 2019 (COVID-19) and it is responsible for the pandemic that we are currently living. COVID-19 causes an aggressive immune response known as cytokine release syndrome or cytokine storm that causes multiorgan failure and in most cases leads to death. In the present work, we aimed to review the molecular mechanisms by which obesity-associated systemic inflammation could cause a more severe clinical presentation of COVID-19. The SARS-CoV-2 infection could potentiate or accelerate the pre-existing systemic inflammatory state of individuals with obesity, via the NLRP3 inflammasome activation and the release of pro-inflammatory cytokines from cells trough Gasdermin-pores commonly found in cell death by pyroptosis.

Coronavirus infection: An immunologists' perspective

“…70 Moreover, changes in glycerophospholipids and sphingolipids are also observed upon IFN production. [66][67][68] Membrane arachidonic acid is augmented, leading to its metabolites' marked production. [70][71][72] Yan et al 71 reported that arachidonic acid and linoleic acid metabolism are amplified in vitro in HCoV-229E-infected epithelial cells, suggesting that the cell response upon viral infection may be combined with the IFN-induced response.…”

“…Most severe cases are observed in the obese and elderly infected patients, presumably due to the subclinical inflammatory condition, which may be prone to generate a deregulated immune response and cytokine storm. Several authors 67,68 have suggested that adipokines are responsible for patients' metabolic response against the SARS‐CoV‐2 virus, which, in turn, induces inflammasome NLP3 activation. The inhibition of fatty acid synthase by orlistat and the AMP‐activated protein kinase (AMPK) activator metformin seem to reduce viral replication of the coronavirus along with a decrease in systemic inflammation 68 .…”

Obesity, Nutrients and the Immune System in the Era of COVID-19

“…These inflammasomes are normally activated during infections with pathogens whose PAMPs are recognized by PRRs such as TLR4 which recognizes, among others, lipopolysaccharides (LPS). Inflammasome activation requires two different signals: One involving activation of the expression of inflammation genes, for example via the nuclear transcription factor-kappa B (NF-kB) pathway, and the other involving phenomena such as oxidative stress or mitochondrial stress [ 14 , 15 ]. Once activated, inflammasomes cleave pro-caspase 1 into caspase 1 which in turn allows the release of the active forms of IL1 and IL-18.…”

“…It targets the angiotensin-converting enzyme 2 (ACE2) which is found in many tissues, particularly in respiratory cells, vascular endothelial cells, and myocardial cells. Once the virus enters the cell, it causes apoptosis of the target cell, triggering activation of the production of pro-inflammatory cytokines and chemokines and the recruitment of inflammatory cells [ 2 ], probably in part via the involvement of the NLRP3 inflammasome [ 15 , 63 ]. The virus also increases the apoptosis of CD3, CD4, and CD8 T cells, which induces lymphopenia and impaired lymphocyte function.…”

Coronavirus disease 2019 severity in obesity: Metabolic dysfunction-associated fatty liver disease in the spotlight

“…To put it simply, CSS comprises the activation of inflammasomes and the following release of pro-inflammatory cytokines like IL-1β and IL-6[ 68 , 69 ]. The inflammasomes are complexes of proteins that reside in macrophages, activated by tool-like receptors binding to a pathogen-associated molecular pattern or damage-associated molecular patterns[ 70 , 71 ]. The liver has the largest macrophage reservoir in the body (the Kupfer cells); and, therefore, the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome can damage this organ and acts as a promising marker of COVID-19 severity in obese patients[ 43 , 72 ].…”