COVID-19 is an inflammatory disease caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus-2), whose manifestations can range from asymptomatic individuals to severe illness characterized by acute respiratory distress syndrome [1]. According to the World Health Organization (https://covid19.who.int/), the disease has accumulated over half-a-billion cases and nearly 7 million deaths worldwide. In the lungs, SARS-CoV-2 replicates and results in virus-mediated tissue damage, which determines the recruitment of immune cells, causing a systemic and local inflammatory response that can persist even after viral clearance 2, 3.

The induction of inflammatory processes in the host cell often requires the involvement of inflammasomes, which are protein platforms that aggregate in the cytosol in response to different stimuli such as microorganism-associated molecular patterns and damage-associated molecular patterns [4]. The inflammasomes consist of at least 3 components: the inflammatory caspase (CASP1, CASP4/11, etc.), an adapter molecule, usually apoptosis-associated speck-like protein with caspase recruitment domain (ASC), and a sensor/receptor protein (NLRP1, NLRP3, NAIP1/2/5, NLRP12, AIM2, etc.). The sensor will determine the specificity of the inflammasome and can be activated in response to microbial products or cellular stress signals. Activation of the sensor through ligand recognition leads to its oligomerization and formation of aggregates of proteins in a microscopic structure called puncta (or speck), a hallmark of active inflammasomes [5]. Such oligomerization allows the recruitment of ASC and CASP1. CASP1 is activated by proteolytic cleavage and promotes the activation of substrates, including the inflammatory cytokines IL-1β (Interleukin-1 beta) and IL-18 (Interleukin-18) and gasdermin-D (GSDMD), a pore-forming protein that induces an inflammatory form of cell death called pyroptosis. The NLRP3 is the most studied inflammasome and can be activated by a variety of stimuli such as potassium efflux, reactive oxygen species (ROS), and lysosomal damage 4, 6, 7. The noncanonical activation of NLRP3 occurs after the initial activation of CASP4 (in humans) or CASP11 (in mice), which induces K+ efflux and, consequently, NLRP3 activation 8, 9, 10, 11. In this paper, we discuss the literature contributing to the understanding of the activation of the NLRP3 inflammasome by SARS-CoV-2 and their participation in the development of severe forms of COVID-19.