(Figure 2).
During lung injury, the NOD-like receptor 3 (NLRP3) inflammasome plays a key role in the innate immune response (Wu et al. 2013). When macrophages sense external pathogens like LPS or viral particles (CoVs not tested yet), activated NLRP3 interacts with apoptosis-associated proteins to form the NLRP3 inflammasome and results in the secretion of the proinflammatory cytokines IL-1β and IL-18 in macrophages to amplify inflammation (Lamkanfi et al. 2012; Guo et al. 2015). NLRP3 activity probably has a balance of protective and damaging action in the lung. It was reported that NLRP3 inhibition in an early infection mouse model increased mortality, but the suppression of NLRP3 at the peak of the infection showed a protective effect (Tate et al. 2016). This outcome supports the potential use of caffeine when COVID-19 related respiratory inflammation is most severe. Furthermore, caffeine was proven to significantly reduce NLRP3 expression and associated caspase cleavage and therefore suppressed the secretion of IL-1β and IL-18 in THP-1 macrophages (Zhao et al. 2019). In addition to that, caffeine was confirmed to inhibit NLRP3 inflammasome activation by suppressing the MAPK/NF-κB signaling in THP-1 macrophages. NLRP1 inflammasome is correlated to lung diseases caused by influenza A virus, bacteria, and syncytial virus (Yang et al. 2006; Tate et al. 2016; Shen et al. 2020). Along with the aforementioned compelling evidence, we propose a potential immunomodulatory role of caffeine in COVID-19 related respiratory inflammation.