The discovery that NLRP3 (which encodes NOD-, LRRand pyrin domain-containing protein 3) gain-offunction mutations cause the dominantly inherited autoinflammatory disease known as cryopyrin-associated periodic syndrome (CAPS) represented a major advance in inflammation research [1][2][3] . CAPS belongs to a group of diseases with varied severity that includes familial cold autoinflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurological cutaneous and articular syndrome (also known as neonatal-onset multisystem inflammatory disorder). Early studies linked NLRP3 to inflammation mediated by the cytokine IL-1 and revealed the involvement of NLRP3 in autoinflammatory diseases, which has been reviewed in depth elsewhere 4,5 . In parallel, the discovery that NLRP1 can form a complex with activated caspase 1 termed the inflammasome 6 , followed by the revelation that NLRP3 can perform a similar function, provided a molecular basis to explain the CAPS phenotype 7 . Beyond the monogenic autoinflammatory diseases in humans, NLRP3 was shown to affect a wide range of disease models in mice, highlighting the potential application of NLRP3-targeted therapies for these diseases.The past decade has witnessed a burgeoning appreciation of inflammasomes as critical innate immune components that orchestrate host immune homeostasis. This Review focuses on the recent advances in our understanding of the activation and intrinsic regulation of the NLRP3 inflammasome machinery, as well as the emerging pharmacological approaches that target the NLRP3 inflammasome and show potential for clinical translation. The NLRP3 inflammasome: an overviewThe NLRP3 inflammasome consists of a sensor (NLRP3), an adaptor (ASC; also known as PYCARD) and an effector (caspase 1). NLRP3 is a tripartite protein that contains an amino-terminal pyrin domain (PYD), a central NACHT domain (domain present in NAIP, CIITA, HET-E and TP1) and a carboxy-terminal leucine-rich repeat domain (LRR domain). The NACHT domain has ATPase activity that is vital for NLRP3 self-association and function 8 , whereas the LRR domain is thought to induce autoinhibition by folding back onto the NACHT domain. ASC has two protein interaction domains, an aminoterminal PYD and a carboxy-terminal caspase recruitment domain (CARD). Full-length caspase 1 has an amino-terminal CARD, a central large catalytic domain (p20) and a carboxy-terminal small catalytic subunit domain (p10). Upon stimulation, NLRP3 oligomerizes through homotypic interactions between NACHT domains (Fig. 1). Oligomerized NLRP3 recruits ASC through homotypic PYD-PYD interactions and nucleates helical ASC filament formation, which also occurs through PYD-PYD interactions. Multiple ASC filaments coalesce into a single macromolecular focus, known as an ASC speck [9][10][11] . Assembled ASC recruits caspase 1 through CARD-CARD interactions and enables proximity-induced caspase 1 self-cleavage and activation. Caspase 1 clustered on ASC self-cleaves at the linker between p20 and p10 to generate a complex of p33 (...

SUMMARY Understanding the negative regulators of anti-viral immune responses will be critical for advancing immune-modulated antiviral strategies. NLRX1, an NLR protein that negatively regulates innate immunity, was previously identified in an unbiased siRNA screen as required for HIV infection. We find that NLRX1 depletion results in impaired nuclear import of HIV-1 DNA in human monocytic cells. Additionally, NLRX1 was observed to reduce type-I interferon (IFN-I) and cytokines in response to HIV-1 reverse-transcribed DNA. NLRX1 sequesters the DNA sensing adaptor STING from interaction with TANK-binding kinase 1 (TBK1), which is a requisite for IFN-1 induction in response to DNA. NLRX1-deficient cells generate an amplified STING-dependent host response to cytosolic DNA, c-di-GMP, cGAMP, HIV-1 and DNA viruses. Accordingly, Nlrx1−/− mice infected with DNA viruses exhibit enhanced innate immunity and reduced viral load. Thus, NLRX1 is a negative regulator of the host innate immune response to HIV-1 and DNA viruses.

Tooth bleaching agents may weaken the tooth structure. Therefore, it is important to minimize any risks of tooth hard tissue damage caused by bleaching agents. The aim of this study was to evaluate the effects of applying 45S5 bioglass (BG) before, after, and during 35% hydrogen peroxide (HP) bleaching on whitening efficacy, physicochemical properties and microstructures of bovine enamel. Seventy-two bovine enamel blocks were prepared and randomly divided into six groups: distilled deionized water (DDW), BG, HP, BG before HP, BG after HP and BG during HP. Colorimetric and microhardness tests were performed before and after the treatment procedure. Representative specimens from each group were selected for morphology investigation after the final tests. A significant color change was observed in group HP, BG before HP, BG after HP and BG during HP. The microhardness loss was in the following order: group HP>BG before HP, BG after HP>BG during HP>DDW, BG. The most obvious morphological alteration of was observed on enamel surfaces in group HP, and a slight morphological alteration was also detected in group BG before HP and BG after HP. Our findings suggest that the combination use of BG and HP could not impede the tooth whitening efficacy. Using BG during HP brought better protective effect than pre/post-bleaching use of BG, as it could more effectively reduce the mineral loss as well as retain the surface integrity of enamel. BG may serve as a promising biomimetic adjunct for bleaching therapy to prevent/restore the enamel damage induced by bleaching agents.

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SUMMARY Appropriate immune responses require a fine balance between immune activation and attenuation. NLRC3, a non-inflammasome-forming member of the NLR innate immune receptor family, attenuates inflammation in myeloid cells and proliferation in epithelial cells. T lymphocytes express the highest amounts of Nlrc3 transcript where its physiologic relevance is unknown. We show that NLRC3 attenuated interferon-γ and TNF expression by CD4+ T cells and reduced T helper 1 (Th1) and Th17 cell proliferation. Nlrc3−/− mice exhibited increased and prolonged CD4+ T cell responses to lymphocytic choriomeningitis virus infection and worsened experimental autoimmune encephalomyelitis (EAE). These functions of NLRC3 were executed in a T-cell-intrinsic fashion: NLRC3 reduced K63-linked ubiquitination of TNF-receptor-associated factor 6 (TRAF6) to limit NF-κB activation, lowered phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), and diminished glycolysis and oxidative phosphorylation. This study reveals an unappreciated role for NLRC3 in attenuating CD4+ T cell signaling and metabolism.

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