Innate Immune Recognition of mtDNA—An Undercover Signal?

In addition to their roles in cellular metabolism and apoptosis, mitochondria function as signaling platforms in the innate immune response. In Nature, West et al. (2015) demonstrate that mitochondrial stress triggers a type I interferon response and confers viral resistance via release of mtDNA and activation of the cGAS–STING pathway

Caspaseâ 1 inflammasomes in infection and inflammation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141971/1/jlb0220.pd

Role of the Nlrp3 Inflammasome in Microbial Infection

The intracellular Nod-like receptor Nlrp3 has emerged as the most versatile innate immune receptor because of its broad specificity in mediating immune response to a wide range of microbial or danger signals. Nlrp3 mediates assembly of the inflammasome complex in the presence of microbial components leading to the activation of caspase-1 and the processing and release of the pro-inflammatory cytokines IL-1β and IL-18. In this review, we give an update on the recent literature examining the role of Nlrp3 inflammasome in response to fungal, bacterial, and viral infections

Reactive oxygen species regulate caspase-11 expression and activation of the non-canonical NLRP3 inflammasome during enteric pathogen infection

Enteropathogenic and enterohemorrhagic bacterial infections in humans are a severe cause of morbidity and mortality. Although NOD-like receptors (NLRs) NOD2 and NLRP3 have important roles in the generation of protective immune responses to enteric pathogens, whether there is crosstalk among NLRs to regulate immune signaling is not known. Here, we show that mice and macrophages deficient in NOD2, or the downstream adaptor RIP2, have enhanced NLRP3-and caspases-11-dependent non-canonical inflammasome activation in a mouse model of enteropathogenic Citrobacter rodentium infection. Mechanistically, NOD2 and RIP2 regulate reactive oxygen species (ROS) production. Increased ROS in Rip2-deficient macrophages subsequently enhances c-Jun N-terminal kinase (JNK) signaling resulting in increased caspase-11 expression and activation, and more non-canonical NLRP3-dependant inflammasome activation. Intriguingly, this leads to protection of the colon epithelium for up to 10 days in Rip2-deficient mice infected with C. rodentium. Our findings designate NOD2 and RIP2 as key regulators of cellular ROS homeostasis and demonstrate for the first time that ROS regulates caspase-11 expression and non-canonical NLRP3 inflammasome activation through the JNK pathway

The NLRC4 inflammasome requires IRF8-dependent production of NAIPs

Activation of the NLRC4 inflammasome is crucial for defense against bacterial species that have flagellin or the type III secretion system (T3SS). We have discovered the role of interferon regulatory factor 8 (IRF8) in mediating NLRC4 inflammasome activation. IRF8 is required for the transcription of genes encoding NAIPs, thereby enabling cellular detection of flagellin or T3SS proteins. In vivo, IRF8 is important for NLRC4 inflammasome–dependent cytokine production, bacterial clearance, and ultimately, host survival. By introducing IRF8 as a player in inflammasome regulation, our study provides a new perspective on that process

Synthesis, biological evaluation and docking studies of (4-aryl-3-methyl-4,5-dihydropyrazolo[3,4-c]pyrazol-1(3aH)-yl)(3-hydroxyquinoxalin-2-yl)methanones

862-866An efficient synthesis of (4-aryl-3-methyl-4,5-dihydropyrazolo[3,4-c]pyrazol-1(3aH)-yl)(3-hydroxyquinoxalin-2-yl) methanones is described via reactions of ethyl acetoacetate with 3-hydroxyquinoxaline-2-carbohydrazide. The structures of the compounds prepared have been determined by spectral analyses

Synthesis, biological evaluation and docking studies of (4-aryl-3-methyl-4,5-dihydropyrazolo[3,4-c]pyrazol-1(3aH)-yl)(3-hydroxyquinoxalin-2-yl)methanones

An efficient synthesis of (4-aryl-3-methyl-4,5-dihydropyrazolo[3,4-c]pyrazol-1(3aH)-yl)(3-hydroxyquinoxalin-2-yl) methanones is described via reactions of ethyl acetoacetate with 3-hydroxyquinoxaline-2-carbohydrazide. The structures of the compounds prepared have been determined by spectral analyses

Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection

Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic, and degenerative diseases in humans. In this study, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida. Genetic deletion or pharmacological inhibition of cathepsin B down-regulated mechanistic target of rapamycin activity and prevented cleavage of the lysosomal calcium channel TRP ML1. These events drove transcription of lysosomal and autophagy genes via transcription factor EB, which increased lysosomal biogenesis and activation of autophagy initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome populations and basic recycling functions in the cell

Chronic TLR stimulation controls NLRP3 inflammasome activation through IL-10 mediated regulation of NLRP3 expression and caspase-8 activation

While the molecular mechanisms promoting activation of the Nod-like Receptor (NLR) family member NLRP3 inflammasome are beginning to be defined, little is known about the mechanisms that regulate the NLRP3 inflammasome. Acute (up to 4 hours) LPS stimulation, followed by ATP is frequently used to activate the NLRP3 inflammasome in macrophages. Interestingly, we observed that the ability of LPS to license NLRP3 is transient, as prolonged (12 to 24 hours) LPS exposure was a relatively ineffective priming stimulus. This suggests that relative to acute LPS, chronic LPS exposure triggers regulatory mechanisms to dampen NLRP3 activation. Transfer of culture supernatants from macrophages stimulated with LPS for 24 hours dramatically reduced ATP- and nigericin-induced NLRP3 inflammasome activation in naive macrophages. We further identified IL-10 as the secreted inflammasome-tolerizing factor that acts in an autocrine manner to control activation of the NLRP3 inflammasome. Finally, we demonstrated that IL-10 dampens NLRP3 expression to control NLRP3 inflammasome activation and subsequent caspase-8 activation. In conclusion, we have uncovered a mechanism by which chronic, but not acute, LPS exposure induces IL-10 to dampen NLRP3 inflammasome activation to avoid overt inflammation