5.4. NOD-like Receptor Pyrin Domain Containing 3
As a well characterized member of the NOD-like receptor family of the innate immune system, NOD-like receptor pyrin domain containing 3 (NLRP3) has been implicated in chronic inflammation associated with obesity, diabetes, cancer, etc. NLRP3 contains a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif. The NLRP3 inflammasome is a multi-protein complex that recruits pro-caspase-1 via the adaptor, apoptosis-associated speck-like protein containing caspase activation and recruitment domains (ASC), and then cleave the cytokine precursor pro-IL-1β into mature IL-1β and then of pro-IL-18 into IL-18 (He, Hara & Nunez, 2016). The following release of other inflammatory cytokines, such as IL-6, TNF- α, prostaglandins and leukotrienes (Abderrazak et al., 2015) contributes to the induction of cytokine storm. Inhibition of NLRP3 has been shown to attenuate the severity of inflammatory diseases (Tomani et al., 2020).
SARS-CoV-2, similar to SARS-CoV, encodes viroporins that have been shown to activate NLRP3 (Chen, Moriyama, Chang & Ichinohe, 2019). Ang II, which can be reduced by ACE2, has been shown to induce the activation of NLRP3 activation in renal tubular epithelial cells (Wen et al., 2016). The binding of S-protein to ACE2 to reduce the availability of ACE2 may increase Ang II, which is a possible mechanism that SARS-CoV-2 induces the activation of NLRP3. Downregulation of ACE2 after SARS-CoV-2 infection has been observed (Zhang, Penninger, Li, Zhong & Slutsky, 2020). The different scenarios of NLRP3 activation in COVID-19 may reflect different level of immune responses (van den Berg & Te Velde, 2020). However, the role of NLRP3 in inflammatory response and effectiveness of NLRP3 inhibitors in COVID-19 patients with hyperinflammation remains to be elucidated.
Colchicine, a currently used anti-gout drug, has anti-inflammatory effect by inhibiting neutrophil chemotaxis and inflammasome. The anti-inflammasome function of colchicine is mediated through its inhibiting activity of NLRP3 inflammasome (Liang, Zhou, Tong, Chen, Ren & Zhao, 2019). Colchicine has been shown to not only reduce the inflammatory cytokines, but also decrease the expression of NLRP3 inflammasome (Fujisue et al., 2017).
Treatment with colchicine reduced cytokines and lowered the rate of clinical deterioration in COVID-19 patients (Deftereos et al., 2020; Gandolfini et al., 2020). In hospitalized COVID-19 patients with pneumonia, treatment with colchicine was associated with reduced mortality and accelerated recovery (Manenti et al., 2021). A recent randomized trial indicated that colchicine 1 mg for 1-3 days followed by 0.5 mg/day for 14 days is effective as a proactive anti-inflammatory therapy in hospitalized COVID-19 patients and viral pneumonia (Mareev et al., 2021). The systemic review of total of eight studies with 5778 COVID-19 patients demonstrated that the administration of colchicine was associated with improved outcomes of COVID-19 (Hariyanto, Halim, Jodhinata, Yanto & Kurniawan, 2021).