Critical Role for Cryopyrin/Nalp3 in Activation of Caspase-1 in Response to Viral Infection and Double-stranded RNA

Abstract

Viral infection induces the production of interleukin (IL)-1␤and IL-18 in macrophages through the activation of caspase-1, but the mechanism by which host cells sense viruses to induce caspase-1 activation is unknown. In this report, we have identified a signaling pathway leading to caspase-1 activation that is induced by doublestranded RNA (dsRNA) and viral infection that is mediated by Cryopyrin/Nalp3. Stimulation of macrophages with dsRNA, viral RNA, or its analog poly(I:C) induced the secretion of IL-1␤ and IL-18 in a cryopyrin-dependent manner. Consistently, caspase-1 activation triggered by poly(I:C), dsRNA, and viral RNA was abrogated in macrophages lacking cryopyrin or the adaptor ASC (apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain) but proceeded normally in macrophages deficient in Toll-like receptor 3 or 7. We have also shown that infection with Sendai and influenza viruses activates the cryopyrin inflammasome. Finally, cryopyrin was required for IL-1␤ production in response to poly(I:C) in vivo. These results identify a mechanism mediated by cryopyrin and ASC that links dsRNA and viral infection to caspase-1 activation resulting in IL-1␤ and IL-18 production.

Inflammasomes and its importance in viral infections

“…The first evidence came from an in vitro study on flock house virus, rotavirus, Sendai virus, and influenza A virus, which demonstrated that viral dsRNA activates caspase-1 in murine macrophages [45]. Later, other RNA viruses, such as encephalomyocarditis virus (ECMV) and vesicular stomatitis virus (VSV), were studied in murine dendritic cells (DCs) and macrophages, and the results indicated that IL-1b secretion was NLRP3-dependent [46].…”

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

“…Pseudomonas aeruginosa, Candida albicans, Saccharomyces cerevisiae, Sendai virus, adenovirus and influenza virus), 30,[33][34][35] or their components (MDP flagellin), [36][37][38] but also by toxins required for pathogen entry into the host cell, such as membrane-disrupting and poreforming compounds (maitotoxin, nigericin, aereolysis, anthrax lethal toxin and alpha-toxin of Staphylococcus aureus) (Figure 2). [39][40][41][42][43] Interestingly, NLRP3 also contributes to the ability of dendritic cells and macrophages to detect endogenous danger molecules released by dying cells.…”

“…[45][46][47] The NLRP3 inflammasome has also been proposed as a sensor of adenoviral DNA, double-stranded RNA and viral RNA. 30,35 PROPOSED MECHANISMS OF INFLAMMASOME ACTIVATION The NLRP3 inflammasome is the best-characterized, but the precise mechanism of NLRP3 activation is still debated. At steady state, inflammasome components are present in the cytosol and their assembly is prevented by auto-inhibitory mechanisms mediated by chaperone proteins.…”

“…Recent studies have suggested a role of inflammasomes in the recognition of viral DNA and RNA during infection. 30,35 For example, NLRP3-deficient mice exhibited limited protection to influenza A infection. Furthermore, an association between NLRP3 polymorphisms and HIV-1 infection has been described; a lower frequency of the 3' UTR SNP rs10754558 G allele was found within HIV-seropositive patients compared to controls.…”

“…However, the precise mechanism of NLRP3-mediated control of HIV-1 has not yet been revealed. Although several independent studies have uncovered a protective function of the inflammasome during viral infections 35,100,101 , others observed that inflammasome activation by certain viruses was mainly crucial for innate and healing response but not for virus control and adaptive immune activation. 102 Thus, the exact mechanism of virus recognition and the possible influence of genetics of inflammasomes on protection from viruses remain unclear.…”