Editorial: NLRP3: immune activator or modulator?

The immune system fights pathogens using innate and adaptive immune mechanisms. The innate immune system is comprised of cellular receptors, called PRRs, that detect PAMPs present on invading pathogens, including viruses [1]. PRRs include sensors, such as TLRs, NLRs, RLRs, and ALRs, to name just a few. The initial innate immune response produces type I and type III IFNs, in addition to proinflammatory cytokines and chemokines that function to recruit immune cells to the site of viral infection. Recruited NK cells, macrophages, and dendritic cells help control the spread of the virus and also initiate the adaptive immune responses to the virus. PRRs are also able to sense endogenous danger-associated molecular patterns, including ATP, monosodium urate, and calcium pyrophosphate dehydrate, which can be biomarkers of trauma and tissue damage [2]. NLRs are cytosolic PRRs that have been linked to autoimmune disease, metabolic disorders, and cancer, in addition to antiviral responses [3]. NLRs contain an N-terminal effector, which is typically a CARD or a PYD [4]. All NLRs also have an NBD and a LRR domain. Many NLRs form an integral part of a large protein complex, called the inflammasome. Activation of inflammasomes results in the induction and secretion of IL-1b and IL-18. Inflammasomes are most often comprised of an NLR, procaspase-1, and ASC, although other inflammasomes comprised of ALR and RLR family members also exist. Several NLR family members have been demonstrated to form inflammasomes, including nucleotide-binding domain and leucine-rich repeat, pyrin domain containing 1 (NLRP1), nucleotide-binding domain and leucine-rich repeat, CARD domain containing 4 (NLRC4) and nucleotidebinding domain and leucine-rich repeat, pyrin domain containing 3 (NLRP3). The NLRP3 protein is comprised of an N-terminal PYD, a central NBD region, and a C-terminal LRR domain. Although it lacks a CARD, by interacting with ASC via its PYD, NLRP3 can recruit procaspase-1 to form the inflammasome complex [5] (Fig. 1A). Activation of the NLRP3 inflammasome by viral infection results in the activation of caspase-1 from procaspase-1, which in turn, results in the caspase-1dependent cleavage of pro-IL-1b and proIL-18 to active IL-1b and IL-18 (Fig. 1A). NLRP3 can be activated upon RNA virus infection, such as infection with influenza A, Sendai virus, respiratory syncytial virus, vesicular stomatitis virus, measles virus, HIV, and hepatitis C virus [6]. NLRP3 is also activated in response to DNA viruses, such as modified vaccinia ankara, adenovirus, varicella-zoster virus, HSV, and Kaposi’s sarcoma-associated herpesvirus [6–9]. HSV-1 and -2 are members of the herpesviridae family. Infection with these viruses is associated with recurrent sores affecting the skin, eyes, mouth, and genitals, as well as more serious conditions, such as herpes encephalitis and meningitis. HSV-1 infection can lead to a condition called herpetic SK, which is a potentially blinding disease caused by HSV-1 corneal infection [10]. HSV-1induced SK is driven by inflammation that is often accompanied by angiogenesis and neovascularization. Destruction of the cornea by both viral replication and immune-mediated damage has been implicated in necrotizing SK, whereas nonnecrotizing SK pathology is primarily driven by the host immune response [10]. In this issue of JLB, Gimenez et al. [11] report that NLRP3 mice display an early onset andmore severe HSV-1-mediated SK than WT mice. SK was visible 3 d earlier in the HSV-1-infected NLRP3 mice compared with WT mice. Surprisingly, the NLRP3 mice displayed increased IL-1b cytokine and increased neutrophil and T cell infiltration into the corneas. In particular, IL-1b levels, but not IL-18, were increased at all time points postinfection of the corneas of NLRP3 mice compared with WT mice. However, caspase-1 activity was similar in both groups. In addition to IL-1b, other cytokines, including IL-6, IL-12, IL-10, MIP2, and TNF-a, were all increased in NLRP3 mice. As noted above, SK is associated with angiogenesis and neovascularization, and Gimenez et al. [11] also described increased