Targeting the NLRP3 Inflammasome in Severe COVID-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the genus Betacoronavirus within the family Coronaviridae. It is an enveloped single-stranded positive-sense RNA virus. Since December of 2019, a global expansion of the infection has occurred with widespread dissemination of coronavirus disease 2019 (COVID-19). COVID-19 often manifests as only mild cold-like symptomatology, but severe disease with complications occurs in 15% of cases. Respiratory failure occurs in severe disease that can be accompanied by a systemic inflammatory reaction characterized by inflammatory cytokine release. In severe cases, fatality is caused by the rapid development of severe lung injury characteristic of acute respiratory distress syndrome (ARDS). Although ARDS is a complication of SARS-CoV-2 infection, it is not viral replication or infection that causes tissue injury; rather, it is the result of dysregulated hyperinflammation in response to viral infection. This pathology is characterized by intense, rapid stimulation of the innate immune response that triggers activation of the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway and release of its products including the proinflammatory cytokines IL-6 and IL-1β. Here we review the literature that describes the pathogenesis of severe COVID-19 and NLRP3 activation and describe an important role in targeting this pathway for the treatment of severe COVID-19.

Keywords: COVID-19; IL-1β; NLRP3 inflammasome; SARS-CoV-2; acute respiratory distress syndrome (ARDS); coronavirus; cytokine release syndrome (CRS); cytokine storm.

Figure 1

The NLRP3 inflammasome mediates lung inflammation in SARS-CoV-2 infection. SARS-CoV-2 is inhaled into the airway and mediates activation of the P2RX7 receptor by release of extracellular ATP. P2RX7 signaling can lead to NLRP3 activation through direct or indirect activation in activated macrophages. Activation of the NLRP3 inflammasome drives the secretion of IL-1β and IL-18 which can result in pyroptosis (programmed cell death). Activation of immune cell subsets, largely through activated macrophages, results in a cascade of massive inflammatory cytokine activation including IL-6, TNF-α, IL-8, IL-10, IL-1RA, and CXCL10 that lead to acute lung injury with acute respiratory distress syndrome, systemic inflammatory response syndrome (SIRS), shock and multiorgan dysfunction, and coagulopathy.