Abstract
Early detection of viruses by the innate immune system is crucial for host defense. The NLRP3 inflammasome, through activation of caspase-1, promotes the maturation of IL-1β and IL-18, which are critical for antiviral immunity and inflammatory response. However, the mechanism by which viruses activate this inflammasome is still debated. Here, we report that the replication of cytopathogenic RNA viruses such as vesicular stomatitis virus (VSV) or encephalomyocarditis virus (EMCV) induced a lytic cell death leading to potassium efflux, the common trigger of NLRP3 inflammasome activation. This lytic cell death was not prevented by a chemical or genetic inhibition of apoptosis, pyroptosis, or necroptosis but required the viral replication. Hence, the viruses that stimulated type I IFNs production after their sensing did not activate NLRP3 inflammasome due to an inhibition of their replication. In contrast, NLRP3 inflammasome activation induced by RNA virus infection was stimulated in IFNAR-deficient or MAVS-deficient cells consequently to an increased viral replication and ensuing lytic cell death. Therefore, in a context of inefficient IFN response, viral replication-induced lytic cell death activates of the NLRP3 inflammasome to fight against infection.
Highlights
Besides directing adaptive immune responses, the pleiotropic cytokines interleukin-1β (IL-1β) and IL-18 play an essential role in inflammatory responses[1]
Previous investigations have demonstrated that some RNA viruses trigger NLRP3 inflammasome activation[14,15], few works have compared in the same study the inflammasome activation through different RNA viruses
In this study, using different RNA viruses, we observed that only replicating viruses with a cytopathogenic effect like vesicular stomatitis virus (VSV) or encephalomyocarditis virus (EMCV) are capable of inducing a significant inflammasome activation
Summary
Besides directing adaptive immune responses, the pleiotropic cytokines interleukin-1β (IL-1β) and IL-18 play an essential role in inflammatory responses[1]. The production of both cytokines is a two-step process, as it is regulated at the transcriptional as well as the posttranslational level. Pro-IL-1β and pro-IL-18 are matured and processed by caspase-1. Activation of this inflammatory caspase is regulated by a complex of proteins called the inflammasome. The cytosolic receptors of the NACHT and LRRcontaining gene (NLR) family are components of most inflammasomes, and these receptors are indirectly coupled to caspase-1 through the adaptor apoptosisassociated speck (ASC-like protein containing a CARD)[2]. Inflammasomes are recognized for their crucial roles in host defense against pathogens[3], but abnormal inflammasome activations are associated with several
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