Can NLRP3 inhibitors improve on dexamethasone for the treatment of COVID-19?

Abstract

Dexamethasone, a corticosteroid, has been approved for use in the treatment of severe COVID-19, which is characterised by hyperinflammation and associated lung damage. However, dexamethasone shows no clinical benefit in the treatment of less severe disease, and prolonged treatment may lead to immunosuppression and an increased risk of opportunistic infections. Hence there is a need for more specific anti-inflammatory therapies which also prevent severe disease. The NLRP3 inflammasome is an intracellular signalling complex which is responsible for the cleavage and release of the cytokines IL-1β and IL-18 and has also been shown to be inhibited by dexamethasone. NLRP3 inflammasome activation is strongly correlated with COVID-19 severity and part of dexamethasone's clinical effect in COVID-19 may be via NLRP3 inhibition. Specific NLRP3 inhibitors are currently undergoing clinical trials for the treatment of COVID-19. In this review, we evaluate the evidence supporting the use of dexamethasone and speculate on the potential use of NLRP3 inhibitors to treat COVID-19 as a more specific approach that may not have the liabilities of dexamethasone.

Keywords: COVID-19; Dexamethasone; Inflammasome; NLRP3; Steroid.

Fig. 1

Mechanics of NLRP3 inflammasome activation. Upon inflammasome stimulation, the central protein NLRP3, consisting of its pyrin domain (PYD), NACHT domain and leucine-rich repeat (LRR) domain, associates with the adaptor protein ASC through PYD-PYD interactions. ASC, in turn, associates with caspase-1 through caspase activation and recruitment domain (CARD) interactions. NEK7 also binds NLRP3 at several surfaces, which aids oligomerization of NLRP3. These interactions lead to assembly of the inflammasome complex, which is followed by autocatalytic cleavage of the effector protein caspase-1 into the active subunits p10 and p20. These subunits carry out the effector functions of the inflammasome complex, including the cleavage of IL-1β into its active form.

Fig. 2

SARS-CoV drives NLRP3 inflammasome activation. Virus-derived dsRNA and ssRNA can be sensed by endosomal TLR3 and TLR7, as well as by the RIG-I-like receptors (RLRs) RIG-I and melanoma differentiation-associated protein 5 (MDA5), which signal through mitochondrial antiviral signaling protein (MAVS) to upregulate proinflammatory gene expression via NF-κB. Pro-IL-1β expression may be upregulated in this manner and is subsequently processed to mature IL-1β by the NLRP3 inflammasome complex. The NLRP3 inflammasome may be activated by specific viral peptides, including open reading frame (ORF) 3a, ORF8B and the envelope (E) protein. IL-1β is released from the cell through the gasdermin D (GSDMD) pore.