Reassessing the role of the NLRP3 inflammasome during pathogenic influenza A virus infection via temporal inhibition

Abstract

The inflammasome NLRP3 is activated by pathogen associated molecular patterns (PAMPs) during infection, including RNA and proteins from influenza A virus (IAV). However, chronic activation by danger associated molecular patterns (DAMPs) can be deleterious to the host. We show that blocking NLRP3 activation can be either protective or detrimental at different stages of lethal influenza A virus (IAV). Administration of the specific NLRP3 inhibitor MCC950 to mice from one day following IAV challenge resulted in hypersusceptibility to lethality. In contrast, delaying treatment with MCC950 until the height of disease (a more likely clinical scenario) significantly protected mice from severe and highly virulent IAV-induced disease. These findings identify for the first time that NLRP3 plays a detrimental role later in infection, contributing to IAV pathogenesis through increased cytokine production and lung cellular infiltrates. These studies also provide the first evidence identifying NLRP3 inhibition as a novel therapeutic target to reduce IAV disease severity.

AIM2 Inflammasome Is Critical for Influenza-Induced Lung Injury and Mortality

“…Together, these results demonstrate that AIM2 deficiency attenuates virus-stimulated proinflammatory response and results in prolonged survival against IAV infections. Similar to other inflammasome studies (39)(40)(41) from the literature, AIM2 deficiency apparently does not affect viral replication (Figs. 4B, 6B).…”

“…1). This might be because of the activation of other inflammasomes such as the NLRP3 inflammasome (6,9,23,(39)(40)(41)44), the well-studied inflammasome in influenza infection. AIM2 deficiency did not alter the expression of NLRP3 or ASC, the common adaptor for AIM2 and NLRP3 inflammasomes, in infected lung tissue or primary cells (data not shown), suggesting that virus could still activate the NLRP3 and other inflammasomes in the absence of AIM2.…”

“…Our results are consistent with the results from Iwasaki's group (23) that NLRP3 deficiency does not alter mouse susceptibility to influenza-induced mortality. Also, a recent study using NLRP3 inhibitor reported that NLRP3 plays a protective role in the early stage of influenza infection, but a detrimental role in the late stage through increased cytokine production and lung cellular infiltrates (39). The NLRP3 inflammasome can be activated by many conditions including a variety of pathogen-and damage-associated molecular patterns and different stresses (45)(46)(47).…”

Regulation and functions of NLRP3 inflammasome during influenza virus infection

“…Consistent with the observations from genetically altered mouse strains, a recent study using MCC950, a specific and potent inhibitor of NLRP3, demonstrated a temporal role for inflammasome activity in host protective responses during influenza virus infection (Tate et al, 2016). Inhibition of inflammasome activity by intranasal treatment with MCC950 from day 1 after infection decreases survival in mice infected with influenza virus (Tate et al, 2016).…”

“…Inhibition of inflammasome activity by intranasal treatment with MCC950 from day 1 after infection decreases survival in mice infected with influenza virus (Tate et al, 2016). However, delayed treatment with MCC950 from day 3 or 7 after infection significantly improves the survival in infected mice (Tate et al, 2016).…”