Interleukin-18 and IL-1β, which are cytokines of the IL-1 family, are synthesized as precursor proteins and activated by the inflammasome via proteolytic processing. IL-1β is only induced in response ...to inflammatory stimuli, but IL-18 is constitutively expressed. However, how IL-18 and IL-1β expression is regulated by different inflammatory signals remains poorly studied. In this study, we found that IL-18 and IL-1β are differentially regulated. Despite being constitutively expressed, IL-18 expression was increased and sustained after stimulation of TLRs. In contrast, IL-1β was induced but not sustained after chronic treatment. Furthermore, type I IFN signaling was essential for induction of IL-18 and macrophages lacking type I IFN signaling were impaired in their ability to promote IL-18 induction. Thus, our findings reveal a fundamental difference in IL-18 and IL-1β regulation and uncover novel mechanisms that are relevant to the inflammatory settings where these proinflammatory cytokines play a critical role.
High-resolution molecular programmes delineating the cellular foundations of mammalian embryogenesis have emerged recently. Similar analysis of human embryos is limited to pre-implantation stages, ...since early post-implantation embryos are largely inaccessible. Notwithstanding, we previously suggested conserved principles of pig and human early development. For further insight on pluripotent states and lineage delineation, we analysed pig embryos at single cell resolution. Here we show progressive segregation of inner cell mass and trophectoderm in early blastocysts, and of epiblast and hypoblast in late blastocysts. We show that following an emergent short naive pluripotent signature in early embryos, there is a protracted appearance of a primed signature in advanced embryonic stages. Dosage compensation with respect to the X-chromosome in females is attained via X-inactivation in late epiblasts. Detailed human-pig comparison is a basis towards comprehending early human development and a foundation for further studies of human pluripotent stem cell differentiation in pig interspecies chimeras.
Inflammasome activation is critical for host defenses against various microbial infections. Activation of the NLRC4 inflammasome requires detection of flagellin or type III secretion system (T3SS) ...components by NLR family apoptosis inhibitory proteins (NAIPs); yet how this pathway is regulated is unknown. Here, we found that interferon regulatory factor 8 (IRF8) is required for optimal activation of the NLRC4 inflammasome in bone-marrow-derived macrophages infected with Salmonella Typhimurium, Burkholderia thailandensis, or Pseudomonas aeruginosa but is dispensable for activation of the canonical and non-canonical NLRP3, AIM2, and Pyrin inflammasomes. IRF8 governs the transcription of Naips to allow detection of flagellin or T3SS proteins to mediate NLRC4 inflammasome activation. Furthermore, we found that IRF8 confers protection against bacterial infection in vivo, owing to its role in inflammasome-dependent cytokine production and pyroptosis. Altogether, our findings suggest that IRF8 is a critical regulator of NAIPs and NLRC4 inflammasome activation for defense against bacterial infection.
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•IRF8 is required for the optimal activation of NLRC4 inflammasome•The expression of Naip1, Naip2, Naip5, and Naip6 is dependent on IRF8•IRF8 is dispensable for the activation of NLRP3, AIM2, and Pyrin inflammasomes•Irf8–/– mice are susceptible to S. Typhimurium and B. thailandensis infection
Optimal activation of NLRC4 inflammasome in response to pathogenic bacteria is dependent on IRF8.
Families of coupled solitons of
PT
-symmetric physical models with gain and loss in fractional dimension and in settings with and without cross-interactions modulation (CIM) are reported. Profiles, ...powers, stability areas, and propagation dynamics of the obtained
PT
-symmetric coupled solitons are investigated. By comparing the results of the models with and without CIM, we find that the stability area of the model with CIM is much broader than the one without CIM. Remarkably, oscillating
PT
-symmetric coupled solitons can also exist in the model of CIM with the same coefficients of the self- and cross-interactions modulations. In addition, the period of these oscillating coupled solitons can be controlled by the linear coupling coefficient.
The inflammasome is an intracellular signaling complex, which on recognition of pathogens and physiological aberration, drives activation of caspase-1, pyroptosis, and the release of the ...pro-inflammatory cytokines IL-1β and IL-18. Bacterial ligands must secure entry into the cytoplasm to activate inflammasomes; however, the mechanisms by which concealed ligands are liberated in the cytoplasm have remained unclear. Here, we showed that the interferon-inducible protein IRGB10 is essential for activation of the DNA-sensing AIM2 inflammasome by Francisella novicida and contributed to the activation of the LPS-sensing caspase-11 and NLRP3 inflammasome by Gram-negative bacteria. IRGB10 directly targeted cytoplasmic bacteria through a mechanism requiring guanylate-binding proteins. Localization of IRGB10 to the bacterial cell membrane compromised bacterial structural integrity and mediated cytosolic release of ligands for recognition by inflammasome sensors. Overall, our results reveal IRGB10 as part of a conserved signaling hub at the interface between cell-autonomous immunity and innate immune sensing pathways.
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•IRGB10 is required for activation of multiple inflammasomes by bacteria•Recruitment of IRGB10 to the bacteria is dependent on GBPs•IRGB10 targeted bacterial cell membrane and mediated bacterial killing•IRGB10 liberated ligands and provided a conserved signaling hub for inflammasomes
Finding the route to the cytoplasm: an interferon-inducible protein localizes to the cell membrane of bacteria, compromising its structural integrity and mediating release of ligands, otherwise inaccessible, for sensing by inflammasomes.
Stimulator of IFN genes (STING) is a cytoplasmic innate immune sensor for cyclic dinucleotides that also serves a dual role as an adaptor molecule for a number of intracellular DNA receptors. ...Although STING has important functions in the host defense against pathogens and autoimmune diseases, its physiological role in cancer is unknown. In this study, we show that STING-deficient mice are highly susceptible to colitis-associated colorectal cancer. Colons of STING-deficient mice exhibit significant intestinal damage and overt proliferation during early stages of tumorigenesis. Moreover, STING-deficient mice fail to restrict activation of the NF-κB- and STAT3-signaling pathways, which leads to increased levels of the proinflammatory cytokines IL-6 and KC. Therefore, our results identified an unexpected and important role for STING in mediating protection against colorectal tumorigenesis.
Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune sensor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic ...tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators was largely intact in Aim2-deficient mice; however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with healthy wild-type mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer.
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•AIM2 is required to mediate protection against colorectal cancer•AIM2 suppresses overt proliferation in enterocytes•AIM2 inhibits expansion of the intestinal stem cell population•Transfer of healthy microbiota dampens tumor development in Aim2-deficient mice
The cytosolic DNA sensor AIM2 regulates stem cell proliferation in the intestinal mucosa in an inflammasome-independent fashion, contributing to a decrease in the likelihood of colorectal cancer development.
We demonstrate that, with the help of a Gaussian potential barrier, dark modes in the form of a local depression (“bubbles”) can be supported by the repulsive Kerr nonlinearity in combination with ...fractional dimension. Similarly, W-shaped modes are supported by a double potential barrier. Families of the modes are constructed in a numerical form, and also by means of the Thomas–Fermi and variational approximations. All these modes are stable, which is predicted by computation of eigenvalues for small perturbations and confirmed by direct numerical simulations.
Nucleotide-binding domain, leucine-rich-repeat-containing proteins (NLRs) are intracellular innate immune sensors of pathogen-associated and damage-associated molecular patterns. NLRs regulate ...diverse biologic processes such as inflammatory responses, cell proliferation and death, and gut microbiota to attenuate tumorigenesis. In a recent publication in Nature, we identified NLRC3 as a negative regulator of PI3K-mTOR signaling and characterized its potential tumor suppressor function. Enterocytes lacking NLRC3 cannot control cellular proliferation because they are unable to suppress activation of PI3K-mTOR signaling pathways. In this Extra-View, we explore possible mechanisms through which NLRC3 regulates cellular proliferation and cell death. Besides interacting with PI3K, NLRC3 associates with TRAF6 and mTOR, confirming our recent finding that NLRC3 negatively regulates the PI3K-mTOR axis. Herein, we show that NLRC3 suppresses c-Myc expression and activation of PI3K-AKT targets FoxO3a and FoxO1 in the colon of Nlrc3
−/−
mice, suggesting that additional signaling pathways contribute to increased cellular proliferation. Moreover, NLRC3 suppresses colorectal tumorigenesis by promoting cellular apoptosis. Genes encoding intestinal stem cell markers BMI1 and OLFM4 are upregulated in the colon of Nlrc3
−/−
mice. Herein, we discuss recent findings and explore mechanisms through which NLRC3 regulates PI3K-mTOR signaling. Our studies highlight the therapeutic potential of modulating NLRC3 to prevent and treat cancer.
We consider one- and two-dimensional (1D and 2D) optical or matter-wave media with a maximum of the local self-repulsion strength at the center, and a minimum at periphery. If the central area is ...broad enough, it supports ground states in the form of flat-floor “bubbles,” and topological excitations, in the form of dark solitons in 1D and vortices with winding number
m
in 2D. Unlike bright solitons, delocalized bubbles and dark modes were not previously considered in this setting. The ground and excited states are accurately approximated by the Thomas–Fermi expressions. The 1D and 2D bubbles, as well as vortices with
m
=
1
, are completely stable, while the dark solitons and vortices with
m
=
2
have nontrivial stability boundaries in their existence areas. Unstable dark solitons are expelled to the periphery, while unstable double vortices are split into rotating pairs of unitary ones. Displaced stable vortices precess around the central point.
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