Colchicine reduces the activation of NLRP3 inflammasome in COVID-19 patients

The first studies evaluating the effect of colchicine on COVID-19 showed its utility in controlling systemic inflammation caused by SARS-CoV-2, resulting in shorter hospital stays and lower mortality [16]. Initial observations were followed by a greater number of studies, observational or controlled, in which this effect of colchicine was not confirmed by the majority [9,10,11]. Moreover, the two most prominent studies on colchicine for COVID-19, one recruiting outpatients [17] and the other recruiting inpatients [18], failed to demonstrate the efficacy of colchicine for their primary endpoints. Based on all studies available, the drug is not recommended as a treatment for COVID-19, regardless of its severity [12,13,14].

We focused on understanding whether the effect of colchicine on the NLRP3 inflammasome could explain the better outcomes we found in our RCT. It is worth mentioning that we studied only one of the multiple potential mechanisms of action of colchicine. We cannot exclude, for example, its negative effects on immune cell migration, neutrophil degranulation, platelet activation, and NETosis. By measuring the serum concentration of Casp1p20 and IL-18, we found that colchicine inhibited the activation of the NLRP3 inflammasome. To the best of our knowledge, this is the first demonstration in an RCT that NLRP3 inflammasome products were systemically reduced under colchicine treatment. We found no difference in serum IL-1β levels. There are potential explanations for this finding: IL-1β can be released in the absence of Casp1p20, especially by neutrophils, cleaved by their cytosolic enzymes [19]; there was a difference in serum IL-1β, but it was not detected [20]; and IL-1β has a very short serum half-life, which may limit its detection [21, 22].

Colchicine reduced systemic inflammation, as evidenced by the reduced serum CRP on Day 2. Colchicine was shown to reduce, among other effects, inflammasome activation in patients with chronic coronary disease [23, 24], acute and recurrent pericarditis [25], and low-grade inflammation related to obesity [26]. There was a concomitant reduction in circulating IL-6 and CRP in all these scenarios.

Previously, our group showed that along with serum Casp1p20, serum IL-18 was correlated with severity and poor clinical outcome in hospitalized COVID-19 patients [3]. Other groups also found the elevation of serum IL-18 as a marker of increased severity and mortality in COVID-19, as reviewed by Qin et al. [27]. In the present study, the reduction in serum IL-18 at Day 2 or 3 occurred in both groups of patients, but with a significant difference only for patients receiving SOC plus colchicine, which provides indirect evidence that the clinical benefit of colchicine is related to NLRP3 inhibition.

Our study has some limitations. Being conducted in one center resulted in a reduced number of individuals. We did not evaluate the function of NLRP3 inflammasome ex vivo nor whether colchicine would reduce the activation of NLRP3 inflammasome in vitro. The effect of colchicine in both situations [28, 29] has already been confirmed in other clinical and laboratory situations, but has not yet been tested in COVID-19. We did not enroll patients with mild symptoms to compare whether the magnitude of systemic inflammation correlates in a broader range with the levels of Casp1p20 and cytokines.

In conclusion, the activation of the NLRP3 inflammasome, as reflected by serum levels of activated Casp1 and IL-18, appeared to be reduced by colchicine in patients with moderate-to-severe COVID-19.

留言 (0)

沒有登入
gif