Colchicine for COVID-19: targeting NLRP3 inflammasome to blunt hyperinflammation

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is capable of inducing the activation of NACHT, leucinerich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome, a macromolecular structure sensing the danger and amplifying the inflammatory response. The main product processed by NLRP3 inflammasome is interleukin (IL)-1β, responsible for the downstream production of IL-6, which has been recognized as an important mediator in coronavirus disease 2019 . Since colchicine is an anti-inflammatory drug with the ability to block NLRP3 inflammasome oligomerization, this may prevent the release of active IL-1β and block the detrimental effects of downstream cytokines, i.e. IL-6. To date, few randomized clinical trials and many observational studies with colchicine have been conducted, showing interesting signals. As colchicine is a nonspecific inhibitor of the NLRP3 inflammasome, compounds specifically blocking this molecule might provide increased advantages in reducing the inflammatory burden and its related clinical manifestations. This may occur through a selective blockade of different steps preceding NLRP3 inflammasome oligomerization as well as through a reduced release of the main cytokines . Since most evidence is based on observational studies, definitive conclusion cannot be drawn and additional studies are needed to confirm preliminary results and further dissect how colchicine and other NLRP3 inhibitors reduce the inflammatory burden and evaluate the timing and duration of treatment.

Interleukin-1 and the NLRP3 inflammasome in COVID-19: Pathogenetic and therapeutic implications

“…The mechanism of action of colchicine relies on its interference with microtubule polymerization that blocks monocyte and neutrophil chemotaxis. 98 More recently, multiple studies have shown that colchicine may exert anti-inflammatory effects through its non-specific inhibitory activity on NLRP3 inflammasome activation . Multiple observational studies exploring colchicine in COVID-19 provided overall encouraging results 99 , 100 , 101 , 102 , 103 , 104 and are summarized elsewhere.…”

The multifaceted roles of NLRP3-modulating proteins in virus infection

“…Colchicine is an anti-inflammatory drug that is currently approved for treatment of acute flares of gout and familial Mediterranean fever, as well as off-label for multiple inflammatory and autoimmune conditions ( 145 ). More recently, it has been looked at as a potential treatment for SARS-CoV-2 ( 146 ).…”

The Potential Role of Growth Differentiation Factor 15 in COVID-19: A Corollary Subjective Effect or Not?

“…Similarly, colchicine increases the expression and the release of hepatic GDF15 [ 32 ]. Different studies confirmed that colchicine decreased COVID-19 severity via the regulation of immune response to SARS-CoV-2 infection [ 72 , 73 , 74 ]. The case series by Al-Kuraishy et al [ 73 ] including COVID-19 patients treated by sequential use of doxycycline in the first week and colchicine in the second week led to significant improvement in clinical outcomes.…”