Activation and Inhibition of the NLRP3 Inflammasome by RNA Viruses

Figures & data

Figure 1 Model of NLRP3 activation. Signals 1 and 2 are both essential for NLRP3 activation. Regarding signal 1, the NF-κB pathway can be activated by TLRs, RLRs and TNF-α signaling, leading to pro-IL-1β and pro-IL-18 upregulation. Regarding signal 2, various PAMPs and DAMPs induce ASC assembly and caspase-1 maturation, which involves NLRP3 activation. In some cases, this is related to the presence of a high concentration of extracellular ATP and subsequent K⁺, Cl⁻ efflux via P2X purinoceptor 7 (P2RX7) channels, pannexin-1 or CLIC channels. Additionally, nigericin, asbestos, and other particulates can induce lysosomal damage, releasing cathepsin B into the cytosol. Moreover, ROS can activate NLRP3 by inducing Ca²⁺ influx through transient receptor potential melastatin 2 (TRPM2) channels. The ALRs can interact with NLRP3 leading to pro-IL-1β and pro-IL-18 upregulation. Lastly, NLRP3 can bind to the dispersed trans-Golgi network (dTGN) via PI4P. Downstream of these processes, IL-1β and IL-18 are released.

Figure 2 Various RNA viruses can activate NLRP3 inflammasomes. EV-71, Zika virus (ZIKV), influenza virus, and hepatitis C virus (HCV), DENV NS2A, NS2B use the ROS-dependent pathway to form the NLRP3 inflammasome complex. Influenza virus can also rupture lysosomes and then activate NLRP3 inflammasomes via a cathepsin B-dependent process. SeV uses MAVS, and EMCV uses mitofusin-2 to activate NLRP3. FMDV 2B, HRV 2B, and EMCV 2B proteins activate NLRP3 via the Ca²⁺ model, while HCV viral RNA, RSV viral RNA, Sars-CoV 3A and influenza M2 use the K⁺ model involving pannexin channels. Influenza M2 and RSV also use the Golgi network to activate NLRP3. Various RNA viruses can inhibit NLRP3 inflammasomes using virus-encoded proteins. The influenza NS1 protein prevents caspase-1 activation and impairs the transcription of pro-inflammatory cytokines to prevent IL-1β and IL-18 release. The influenza A PB1-F2 protein impairs mitochondria in order to inhibit NLRP3 activation. The measles virus (MV) V protein prevents the transcription of IFN-α/β. The SeV V protein prevents NLRP3-mediated ASC oligomerization. The EV-71 2A and 3C proteases directly cleave NLRP3.

Table 1 Summary of the Components of RNA Viruses That Affect the NLRP3 Inflammasome

RNA Viruses That Activate the NLRP3 Inflammasome
Virus	Activator	Possible Mechanism	References
Influenza virus	vRNA	ROS/M2 ion channel	[29,109]
Enterovirus 71 (EV-71)	vRNA	ROS	[147]
Rift Valley fever virus (RVFV)	vRNA	MAVS	[85]
Respiratory syncytial virus (RSV)	vRNA	ROS and K^+ efflux	[112]
Newcastle disease virus (NDV)	vRNA	ROS	[114]
Human immunodeficiency virus (HIV)	vRNA		[122]
Measles virus (MV)	vRNA		[2]
Sendai virus (SeV)	vRNA	MAVS	[119]
Zika virus (ZIKV)	NS5 protein	ROS	[125]
Dengue virus (DENV)	NS2A, NS2B protein	ROS and Ca^2+ influx	[135]
Severe acute respiratory syndrome coronavirus (Sars-CoV)	3A viroporin	ROS, Ca^2+ influx and K^+ efflux	[105]
Encephalomyocarditis virus (EMCV)	2B protein	ROS	[142,145]
Human rhinovirus (HRV)	2B protein	NLRC5 and Ca^2+ influx	[149]
Foot and mouth disease virus (FMDV)	2B protein	Ca^2+ influx and K^+ efflux	[152]
RNA Viruses That Inhibit the NLRP3 Inflammasome
Virus	Inhibitor	Possible Mechanism	References
Influenza virus	NS1 protein	Blocks caspase-1 activation	[155,156]
Measles virus (MV)	V protein	Blocks IL-1 β secretion	[117]
Sendai virus (SeV)	V protein	Blocks NLRP3-dependent ASC oligomerization	[164]
Enterovirus 71 (EV-71)	2A and 3C proteases	Directly cleave NLRP3	[147]

Notes: Influenza virus, EV-71, RVFV, RSV, NDV, HIV, MV, and SeV activate the NLRP3 inflammasome through their viral RNA, whereas ZIKV, EMCV, HRV, DENV Sars-CoV and FMDV use virus-encoded proteins to activate the NLRP3 inflammasome. Influenza virus, EV-71, RVFV, and EMCV activate the NLRP3 inflammasome through the ROSmediated pathway, DENV uses both ROS and Ca²⁺ influx, RSV uses ROS and K⁺ efflux, SeV uses MAVS, Sars-CoV uses ROS, Ca²⁺ influx and K+ effluxes, FMDV uses Ca²⁺ influx and K⁺ effluxes, and HRV uses NLRC5 and Ca²⁺ influx. Influenza virus, MV, SeV, and EV-71 inhibit the NLRP3 inflammasome using virus-encoded proteins, blocking various cytokines.

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