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https://www.readbyqxmd.com/read/28093447/inflammasomes-and-cancer
#1
Rajendra Karki, Si Ming Man, Thirumala-Devi Kanneganti
Inflammation affects all stages of tumorigenesis. A key signaling pathway leading to acute and chronic inflammation is through activation of the caspase-1 inflammasome. Inflammasome complexes are assembled on activation of certain nucleotide-binding domain, leucine-rich repeat-containing proteins (NLR), AIM2-like receptors, or pyrin. Of these, NLRP1, NLRP3, NLRC4, NLRP6, and AIM2 influence the pathogenesis of cancer by modulating innate and adaptive immune responses, cell death, proliferation, and/or the gut microbiota...
January 16, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/27998728/il-1%C3%AE-and-caspase-1-drive-autoinflammatory-disease-independently-of-il-1%C3%AE-or-caspase-8-in-a-mouse-model-of-familial-mediterranean-fever
#2
Deepika Sharma, Bhesh Raj Sharma, Peter Vogel, Thirumala-Devi Kanneganti
Mutations in the gene encoding pyrin are associated with autoinflammatory disorder Familial Mediterranean Fever (FMF). A FMF-knock-in mouse strain that expresses chimeric pyrin protein with a V726A mutation (Mefv(V726A/V726A)) was generated to model human FMF. This mouse strain shows an autoinflammatory disorder that is prevented by genetic deletion of IL-1 (IL-1) receptor or apoptosis-associated speck-like protein containing a CARD (ASC). ASC-mediated cell death leads to the release of IL-1α and IL-1β, both of which signal through IL-1 receptor...
December 17, 2016: American Journal of Pathology
https://www.readbyqxmd.com/read/27951586/nlrc3-is-an-inhibitory-sensor-of-pi3k-mtor-pathways-in-cancer
#3
Rajendra Karki, Si Ming Man, R K Subbarao Malireddi, Sannula Kesavardhana, Qifan Zhu, Amanda R Burton, Bhesh Raj Sharma, Xiaopeng Qi, Stephane Pelletier, Peter Vogel, Philip Rosenstiel, Thirumala-Devi Kanneganti
NLRs (nucleotide-binding domain and leucine-rich repeats) belong to a large family of cytoplasmic sensors that regulate an extraordinarily diverse range of biological functions. One of these functions is to contribute to immunity against infectious diseases, but dysregulation of their functional activity leads to the development of inflammatory and autoimmune diseases. Cytoplasmic innate immune sensors, including NLRs, are central regulators of intestinal homeostasis. NLRC3 (also known as CLR16.2 or NOD3) is a poorly characterized member of the NLR family and was identified in a genomic screen for genes encoding proteins bearing leucine-rich repeats (LRRs) and nucleotide-binding domains...
December 12, 2016: Nature
https://www.readbyqxmd.com/read/27917412/zbp1-dai-is-an-innate-sensor-of-influenza-virus-triggering-the-nlrp3-inflammasome-and-programmed-cell-death-pathways
#4
Teneema Kuriakose, Si Ming Man, R K Subbarao Malireddi, Rajendra Karki, Sannula Kesavardhana, David E Place, Geoffrey Neale, Peter Vogel, Thirumala-Devi Kanneganti
The interferon-inducible protein Z-DNA binding protein 1 (ZBP1, also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1) was identified as a dsDNA sensor, which instigates innate immune responses. However, this classification has been disputed and whether ZBP1 functions as a pathogen sensor during an infection has remained unknown. Herein, we demonstrated ZBP1-mediated sensing of the influenza A virus (IAV) proteins NP and PB1, triggering cell death and inflammatory responses via the RIPK1-RIPK3-Caspase-8 axis...
August 5, 2016: Science Immunology
https://www.readbyqxmd.com/read/27892465/distinct-role-of-il-1%C3%AE-in-instigating-disease-in-sharpin-cpdm-mice
#5
Prajwal Gurung, Bhesh Raj Sharma, Thirumala-Devi Kanneganti
Mice deficient in SHARPIN (Sharpin(cpdm) mice), a member of linear ubiquitin chain assembly complex (LUBAC), develop severe dermatitis associated with systemic inflammation. Previous studies have demonstrated that components of the TNF-signaling pathway, NLRP3 inflammasome and IL-1R signaling are required to provoke skin inflammation in Sharpin(cpdm) mice. However, whether IL-1α or IL-1β, both of which signals through IL-1R, instigates skin inflammation and systemic disease is not known. Here, we have performed extensive cellular analysis of pre-diseased and diseased Sharpin(cpdm) mice and demonstrated that cellular dysregulation precedes skin inflammation...
November 28, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27786577/regulation-of-lysosomal-dynamics-and-autophagy-by-ctsb-cathepsin-b
#6
Si Ming Man, Thirumala-Devi Kanneganti
Cysteine cathepsins are responsible for driving proteolytic degradation within the lysosome and in the extralysosomal milieu. They also have an integral role in autophagy, antigen presentation, cellular stress signaling, metabolism and lysosome-dependent cell death. Here, we discuss our findings on the role of CTSB (cathepsin B), a member of the cysteine cathepsin family, in regulating the bioavailability of lysosomes and autophagosomes and consider how this regulatory response influences host susceptibility to infectious agents...
December 2016: Autophagy
https://www.readbyqxmd.com/read/27775548/il-33-regulates-the-iga-microbiota-axis-to-restrain-il-1%C3%AE-dependent-colitis-and-tumorigenesis
#7
Ankit Malik, Deepika Sharma, Qifan Zhu, Rajendra Karki, Clifford S Guy, Peter Vogel, Thirumala-Devi Kanneganti
Inflammatory bowel diseases (IBD) affect over 5 million individuals in the industrialized world, with an increasing incidence rate worldwide. IBD also predisposes affected individuals to development of colorectal cancer, which is a leading cause of cancer-related deaths in adults. Mutations in genes encoding molecules in the IL-33 signaling pathway are associated with colitis and colitis-associated cancer (CAC), but how IL-33 modulates gut homeostasis is unclear. Here, we have shown that Il33-deficient mice are highly susceptible to colitis and CAC...
December 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27693356/irgb10-liberates-bacterial-ligands-for-sensing-by-the-aim2-and-caspase-11-nlrp3-inflammasomes
#8
Si Ming Man, Rajendra Karki, Miwa Sasai, David E Place, Sannula Kesavardhana, Jamshid Temirov, Sharon Frase, Qifan Zhu, R K Subbarao Malireddi, Teneema Kuriakose, Jennifer L Peters, Geoffrey Neale, Scott A Brown, Masahiro Yamamoto, Thirumala-Devi Kanneganti
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...
October 6, 2016: Cell
https://www.readbyqxmd.com/read/27624090/rewiring-cellular-metabolism-via-the-akt-mtor-pathway-contributes-to-host-defence-against-mycobacterium-tuberculosis-in-human-and-murine-cells
#9
Ekta Lachmandas, Macarena Beigier-Bompadre, Shih-Chin Cheng, Vinod Kumar, Arjan van Laarhoven, Xinhui Wang, Anne Ammerdorffer, Lily Boutens, Dirk de Jong, Thirumala-Devi Kanneganti, Mark S Gresnigt, Tom H M Ottenhoff, Leo A B Joosten, Rinke Stienstra, Cisca Wijmenga, Stefan H E Kaufmann, Reinout van Crevel, Mihai G Netea
Cells in homeostasis metabolize glucose mainly through the tricarboxylic acid cycle and oxidative phosphorylation, while activated cells switch their basal metabolism to aerobic glycolysis. In this study, we examined whether metabolic reprogramming toward aerobic glycolysis is important for the host response to Mycobacterium tuberculosis (Mtb). Through transcriptional and metabolite analysis we show that Mtb induces a switch in host cellular metabolism toward aerobic glycolysis in human peripheral blood mononuclear cells (PBMCs)...
November 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/27551156/cathepsin-b-modulates-lysosomal-biogenesis-and-host-defense-against-francisella-novicida-infection
#10
Xiaopeng Qi, Si Ming Man, R K Subbarao Malireddi, Rajendra Karki, Christopher Lupfer, Prajwal Gurung, Geoffrey Neale, Clifford S Guy, Mohamed Lamkanfi, Thirumala-Devi Kanneganti
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 TRPML1...
September 19, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27418355/interferon-inducible-guanylate-binding-proteins-at-the-interface-of-cell-autonomous-immunity-and-inflammasome-activation
#11
REVIEW
Si Ming Man, David E Place, Teneema Kuriakose, Thirumala-Devi Kanneganti
Guanylate-binding proteins (GBPs) are essential components of cell-autonomous immunity. In response to IFN signaling, GBPs are expressed in the cytoplasm of immune and nonimmune cells, where they unleash their antimicrobial activity toward intracellular bacteria, viruses, and parasites. Recent studies have revealed that GBPs are essential for mediating activation of the caspase-1 inflammasome in response to the gram-negative bacteria Salmonella enterica serovar Typhimurium, Francisella novicida, Chlamydia muridarum, Chlamydia trachomatis, Legionella pneumophila, Vibrio cholerae, Enterobacter cloacae, and Citrobacter koseri During infection with vacuolar-restricted gram-negative bacteria, GBPs disrupt the vacuolar membrane to ensure liberation of LPS for cytoplasmic detection by caspase-11 and the noncanonical NLRP3 inflammasome...
January 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/27325789/the-cell-biology-of-inflammasomes-mechanisms-of-inflammasome-activation-and-regulation
#12
REVIEW
Deepika Sharma, Thirumala-Devi Kanneganti
Over the past decade, numerous advances have been made in the role and regulation of inflammasomes during pathogenic and sterile insults. An inflammasome complex comprises a sensor, an adaptor, and a zymogen procaspase-1. The functional output of inflammasome activation includes secretion of cytokines, IL-1β and IL-18, and induction of an inflammatory form of cell death called pyroptosis. Recent studies have highlighted the intersection of this inflammatory response with fundamental cellular processes. Novel modulators and functions of inflammasome activation conventionally associated with the maintenance of homeostatic biological functions have been uncovered...
June 20, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27291827/dock2-confers-immunity-and-intestinal-colonization-resistance-to-citrobacter-rodentium-infection
#13
Zhiping Liu, Si Ming Man, Qifan Zhu, Peter Vogel, Sharon Frase, Yoshinori Fukui, Thirumala-Devi Kanneganti
Food poisoning is one of the leading causes of morbidity and mortality in the world. Citrobacter rodentium is an enteric pathogen which attaches itself to enterocytes and induces attachment and effacing (A/E) lesions. The ability of the bacterium to cause infection requires subversion of the host actin cytoskeleton. Rac-dependent actin polymerization is activated by a guanine nucleotide exchange factor known as Dedicator of cytokinesis 2 (DOCK2). However, the role of DOCK2 in infectious disease is largely unexplored...
June 13, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27267764/autoinflammatory-skin-disorders-the-inflammasomme-in-focus
#14
REVIEW
Prajwal Gurung, Thirumala-Devi Kanneganti
Autoinflammatory skin disorders are a group of heterogeneous diseases that include diseases such as cryopyrin-associated periodic syndrome (CAPS) and familial Mediterranean fever (FMF). Therapeutic strategies targeting IL-1 cytokines have proved helpful in ameliorating some of these diseases. While inflammasomes are the major regulators of IL-1 cytokines, inflammasome-independent complexes can also process IL-1 cytokines. Herein, we focus on recent advances in our understanding of how IL-1 cytokines, stemming from inflammasome-dependent and -independent pathways are involved in the regulation of skin conditions...
July 2016: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/27148834/microbiota-and-caspase-1-caspase-8-regulate-il-1%C3%AE-mediated-bone-disease
#15
Farrah C Phillips, Prajwal Gurung, Thirumala-Devi Kanneganti
A leucine-to-proline missense mutation at residue 98 in the proline-serine-threonine phosphatase interacting protein 2 (Pstpip2) gene leads to autoinflammatory disease that is characterized by splenomegaly, necrosis, and spontaneous development of osteomyelitis in mice (Pstpip2(cmo)). Disease progression in these mice resembles that of chronic recurrent multifocal osteomyelitis in humans. Our group and others have shown that disease progression in Pstpip2(cmo) mice is mediated by the cytokine IL-1β, independently of inflammasomes or IL-1α...
July 3, 2016: Gut Microbes
https://www.readbyqxmd.com/read/27101991/autophagy-suppresses-host-adaptive-immune-responses-toward-borrelia-burgdorferi
#16
Kathrin Buffen, Marije Oosting, Yang Li, Thirumala-Devi Kanneganti, Mihai G Netea, Leo A B Joosten
We have previously demonstrated that inhibition of autophagy increased the Borrelia burgdorferi induced innate cytokine production in vitro, but little is known regarding the effect of autophagy on in vivo models of Borrelia infection. Here, we showed that ATG7-deficient mice that were intra-articular injected with Borrelia spirochetes displayed increased joint swelling, cell influx, and enhanced interleukin-1β and interleukin-6 production by inflamed synovial tissue. Because both interleukin-1β and interleukin-6 are linked to the development of adaptive immune responses, we examine the function of autophagy on Borrelia induced adaptive immunity...
September 2016: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/27071119/nlrp3-inflammasome-plays-a-redundant-role-with-caspase-8-to-promote-il-1%C3%AE-mediated-osteomyelitis
#17
Prajwal Gurung, Amanda Burton, Thirumala-Devi Kanneganti
Missense mutation in the proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) gene results in the development of spontaneous chronic bone disease characterized by bone deformity and inflammation that is reminiscent of patients with chronic multifocal osteomyelitis (cmo). Interestingly, this disease is specifically mediated by IL-1β but not IL-1α. The precise molecular pathways that promote pathogenic IL-1β production inPstpip2(cmo)mice remain unidentified. Furthermore, how IL-1β provokes inflammatory bone disease inPstpip2(cmo)mice is not known...
April 19, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27056948/dna-sensing-inflammasomes-regulation-of-bacterial-host-defense-and-the-gut-microbiota
#18
REVIEW
Si Ming Man, Rajendra Karki, Thirumala-Devi Kanneganti
DNA sensors are formidable immune guardians of the host. At least 14 cytoplasmic DNA sensors have been identified in recent years, each with specialized roles in driving inflammation and/or cell death. Of these, AIM2 is a sensor of dsDNA, and forms an inflammasome complex to activate the cysteine protease caspase-1, mediates the release of the proinflammatory cytokines IL-1β and IL-18, and induces pyroptosis. The inflammasome sensor NLRP3 can also respond to DNA in the forms of oxidized mitochondrial DNA and the DNA derivative RNA:DNA hybrids produced by bacteria, whereas the putative inflammasome sensor IFI16 responds to viral DNA in the nucleus...
June 2016: Pathogens and Disease
https://www.readbyqxmd.com/read/27032699/immune-responses-against-protozoan-parasites-a-focus-on-the-emerging-role-of-nod-like-receptors
#19
REVIEW
Prajwal Gurung, Thirumala-Devi Kanneganti
Nod-like receptors (NLRs) have gained attention in recent years because of the ability of some family members to assemble into a multimeric protein complex known as the inflammasome. The role of NLRs and the inflammasome in regulating innate immunity against bacterial pathogens has been well studied. However, recent studies show that NLRs and inflammasomes also play a role during infections caused by protozoan parasites, which pose a significant global health burden. Herein, we review the diseases caused by the most common protozoan parasites in the world and discuss the roles of NLRs and inflammasomes in host immunity against these parasites...
August 2016: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/26962937/type-i-interferon-keeps-il-1%C3%AE-in-check
#20
COMMENT
Si Ming Man, Thirumala-Devi Kanneganti
Type I interferons have diametric roles in the host defense against pathogens. In this issue of Cell Host & Microbe, Castiglia et al. (2016) demonstrate that type I interferons produced during Streptococcus pyogenes infection are required to prevent inflammation-associated tissue damage and host lethality driven by the pro-inflammatory cytokine IL-1β.
March 9, 2016: Cell Host & Microbe
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