Immunosuppressants
Three clinical trials are recruiting COVID-19 patients to test the
efficacy of the immunosuppressant sirolimus(NCT04341675, NCT04371640 and
NCT04374903), whereas no clinical study on the calcineurin inhibitor
cyclosporine in COVID-19 has been recorded, despite it has been
hypothesized as potential candidate for SARS-CoV-2 infection (Cure,
Kucuk & Cumhur Cure, 2020). Both the immunosuppressants can interfere
with NLRP3 inflammasome. Sirolimus inhibits NLRP3 inflammasome
activation in macrophages through autophagy induction (Ko, Yoon, Lee &
Oh, 2017), whereas cyclosporine targets cyclophilin D to avoid the
opening of mitochondria permeability transition pore (MPT), which is
strictly involved in NLRP3 inflammasome activation (Iyer et al., 2013).
Another well-known NLRP3 inhibitor included in several clinical
protocols for COVID-19 patients is the classical anti-mitotic drug
colchicine, with at least ten ongoing clinical trials (NCT04328480,
NCT04322682, 2020-001841-38, NCT04392141, 2020-001511-25, NCT04322565,
NCT04375202, NCT04360980, 2020-001603-16, NCT04363437) and 3 others
ready to start (NCT04367168, NCT04355143, NCT04326790). Several
mechanisms have been proposed to explain how colchicine can suppress
NLRP3 inflammasome activation. First, colchicine can inhibit the
expression of pyrin gene, avoiding the assembly of the NLRP3
inflammasome complex (Nidorf, Eikelboom & Thompson, 2014). Second,
colchicine inhibits activation of caspase-1 and mature IL-1β (Otani et
al., 2016). Third, colchicine inhibits P2X7-induced pore formation, a
key step in NLRP3 inflammasome activation following ATP exposure
(Marques-da-Silva, Chaves, Castro, Coutinho-Silva & Guimaraes, 2011).
Other interesting small molecules with immunomodulatory properties,
already proposed for COVID-19 infection and with documented modulatory
activity on NLRP3 inflammasome, are the Janus kinase (JAK) inhibitor
baricitinib and the Bruton’s tyrosine kinase (BTK) inhibitor
acalabrutinib. A study on baricitinib has already been concluded with
interesting results (NCT04358614) and others are recruiting patients for
both the treatments (Baricitinib: NCT04320277 and NCT04390464;
Acalabrutinib: NCT04346199 and NCT04380688). Experimental evidence for
key roles of the JAK and BTK cascades in either activation of the NLRP3
inflammasome and diabesity pathogenesis have been reported in the
literature (Collotta et al., 2020; Furuya et al., 2018)
Up to nowadays six clinical trials (NCT04347980, NCT04325061,
NCT04395105, NCT04344730, NCT04360876, NCT04327401), reported on
clinicaltrials.gov are recruiting patients to test the efficacy of the
corticosteroid dexamethasone , whose beneficial effects in airway
inflammation has been recently demonstrated to involve lung inhibition
of the activity of NLRP3 inflammasome and the release of IL-1β and IL-18
(Guan, Ma, Fan, Chen, Miao & Wu, 2020).