Activation of caspase-1 by the NLRP3 inflammasome regulates the NADPH oxidase NOX2 to control phagosome function

Phagocytosis is a fundamental cellular process that is pivotal for immunity as it coordinates microbial killing, innate immune activation and antigen presentation. An essential step in this process is phagosome acidification, which regulates a number of functions of these organelles that allow them to participate in processes essential to both innate and adaptive immunity. Here we report that acidification of phagosomes containing Gram-positive bacteria is regulated by the NLRP3-inflammasome and caspase-1. Active caspase-1 accumulates on phagosomes and acts locally to control the pH by modulating buffering by the NADPH oxidase NOX2. These data provide insight into a mechanism by which innate immune signals can modify cellular defenses and establish a new function for the NLRP3-inflammasome and caspase-1 in host defense

Inflammasomes and anti-viral immunity

Type I Interferons are the hallmark cytokines deployed during infection to combat invading viruses. However, inflammatory cytokines such as Interleukin (IL)-1beta and IL-18 also play important roles in anti-viral defenses. The activity of IL-1beta and IL18 are regulated at the level of expression, processing, and secretion. Several classes of innate immune receptors control the expression of these cytokines, which must then be proteolytically processed via caspase-1. In this review, we provide an overview of how caspase-1-activating inflammasomes participate during viral infections and their role in regulating anti-viral immunity

Inflammasome Complexes: Emerging Mechanisms and Effector Functions

Canonical activation of the inflammasome is critical to promote caspase-1-dependent maturation of the proinflammatory cytokines IL-1beta and IL-18, as well as to induce pyroptotic cell death in response to pathogens and endogenous danger signals. Recent discoveries, however, are beginning to unveil new components of the inflammasome machinery as well as the full spectrum of inflammasome functions, extending their influence beyond canonical functions to regulation of eicosanoid storm, autophagy, and metabolism. In addition, the receptor components of the inflammasome can also regulate diverse biological processes, such as cellular proliferation, gene transcription, and tumorigenesis, all of which are independent of their inflammasome complex-forming capabilities. Here, we review these recent advances that are shaping our understanding of the complex biology of the inflammasome and its constituents

Innate immune sensing of DNA viruses

DNA viruses are a significant contributor to human morbidity and mortality. The immune system protects against viral infections through coordinated innate and adaptive immune responses. While the antigen-specific adaptive mechanisms have been extensively studied, the critical contributions of innate immunity to anti-viral defenses have only been revealed in the very recent past. Central to these anti-viral defenses is the recognition of viral pathogens by a diverse set of germ-line encoded receptors that survey nearly all cellular compartments for the presence of pathogens. In this review, we discuss the recent advances in the innate immune sensing of DNA viruses and focus on the recognition mechanisms involved

Catenin\u27 on to nucleic acid sensing

Many pathogens induce a type I interferon response via a pathway dependent on the kinase TBK1 and transcription factor IRF3. However, LRRFIP1, a cytosolic sensor of DNA and RNA, triggers interferon production by a β-catenin-dependent signal

Inflammasomes: Intracellular detection of extracellular bacteria

The non-canonical inflammasome triggers host cell death and inflammation upon recognition of cytosolic LPS. A recent report in Cell now shows that Outer Membrane Vesicles (OMVs) of extracellular Gram-negative bacteria can deliver LPS into the host cell cytosol

Aim2 deficiency stimulates the expression of IFN-inducible Ifi202, a lupus susceptibility murine gene within the Nba2 autoimmune susceptibility locus

Murine Aim2 and p202 proteins (encoded by the Aim2 and Ifi202 genes) are members of the IFN-inducible p200 protein family. Both proteins can sense dsDNA in the cytoplasm. However, upon sensing dsDNA, only the Aim2 protein through its pyrin domain can form an inflammasome to activate caspase-1 and induce cell death. Given that the p202 protein has been predicted to inhibit the activation of caspase-1 by the Aim2 protein and that increased levels of the p202 protein in female mice of certain strains are associated with lupus susceptibility, we compared the expression of Aim2 and Ifi202 genes between Aim2-deficient and age-matched wild-type mice. We found that the Aim2 deficiency in immune cells stimulated the expression of Ifi202 gene. The increased levels of the p202 protein in cells were associated with increases in the expression of IFN-beta, STAT1, and IFN-inducible genes. Moreover, after knockdown of Aim2 expression in the murine macrophage cell line J774.A1, IFN-beta treatment of cells robustly increased STAT1 protein levels (compared with those of control cells), increased the activating phosphorylation of STAT1 on Tyr-701, and stimulated the activity of an IFN-responsive reporter. Notably, the expression of Aim2 in non-lupus-prone (C57BL/6 and B6.Nba2-C) and lupus-prone (B6.Nba2-ABC) splenic cells and in a murine macrophage cell line that overexpressed p202 protein was found to be inversely correlated with Ifi202. Collectively, our observations demonstrate an inverse correlation between Aim2 and p202 expressions. We predict that defects in Aim2 expression within immune cells contribute to increased susceptibility to lupus

Bacterial Outer Membrane Vesicles Mediate Cytosolic Localization of LPS and Caspase-11 Activation

Dalam buku ini penulis mencoba membahas dasar ilmu sosial budaya sampai dengan sosial budaya yang memfokuskan dalam kesehatan khususnya dalam kehidupan.404 hlm.: ilus.; 21 c