DOCSLIB.ORG

Inflammasome-Independent and Atypical Processing of IL-1Β

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Inflammasome-Independent and Atypical Processing of IL-1Β Inflammasome-Independent and Atypical Processing of IL-1 β Contributes to Acid Aspiration−Induced Acute Lung Injury This information is current as Yoshiko Mizushina, Tadayoshi Karasawa, Kenichi Aizawa, of September 23, 2021. Hiroaki Kimura, Sachiko Watanabe, Ryo Kamata, Takanori Komada, Naoko Mato, Tadashi Kasahara, Shinichiro Koyama, Masashi Bando, Koichi Hagiwara and Masafumi Takahashi J Immunol published online 20 May 2019 Downloaded from http://www.jimmunol.org/content/early/2019/05/17/jimmun ol.1900168 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 23, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published May 20, 2019, doi:10.4049/jimmunol.1900168 The Journal of Immunology Inflammasome-Independent and Atypical Processing of IL-1b Contributes to Acid Aspiration–Induced Acute Lung Injury Yoshiko Mizushina,*,†,‡ Tadayoshi Karasawa,* Kenichi Aizawa,x Hiroaki Kimura,* Sachiko Watanabe,* Ryo Kamata,* Takanori Komada,* Naoko Mato,† Tadashi Kasahara,* Shinichiro Koyama,‡ Masashi Bando,† Koichi Hagiwara,† and Masafumi Takahashi* Inflammation plays a pivotal role in the pathophysiology of gastric aspiration–induced acute lung injury (ALI). However, its mechanism remains unclear. In this study, we investigated the role of NLRP3 inflammasome–driven IL-1b production in a mouse model of acid aspiration–induced inflammation and ALI. Acid aspiration–induced inflammatory responses and ALI in wild-type mice were significantly attenuated in IL-1b2/2 mice, but not NLRP32/2 mice. In vitro experiments revealed that severe acidic stress (pH 1.75) induced the processing of pro–IL-1b into its 18-kDa mature form (p18–IL-1b), which was different from the caspase-1–processed 17-kDa form (p17–IL-1b), in human THP-1 macrophages and primary murine macrophages. Deficiency of Downloaded from NLRP3 and caspase-1 had no effect on acidic stress–produced IL-1b. The production of IL-1b by severe acidic stress was prevented by inhibitors of serine proteases [4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride], but not of cysteine proteases (E-64), cathepsin G, or inflammasome. The cathepsin D inhibitor pepstatin A inhibited IL-1b production induced by mild acidic stress (pH 6.2) or lactic acid, but not severe acidic stress. Using mass spectrometry and processing-site mutants of pro–IL-1b,we identified D109 as a novel cleavage site of pro–IL-1b in response to severe acidic stress and calculated the theoretical molecular mass of the mature form to be 18.2 kDa. The bioactivity of acidic stress–produced IL-1b was confirmed by its ability to promote http://www.jimmunol.org/ p38 phosphorylation and chemokine upregulation in alveolar epithelial cells. These findings demonstrate a novel mechanism of acid-induced IL-1b production and inflammation independent of NLRP3 inflammasome and provide new insights into the therapeutic strategies for aspiration pneumonitis and ALI. The Journal of Immunology, 2019, 203: 000–000. astric aspiration pneumonitis is defined as an acute lung role in the progression of acid aspiration–induced ALI (1, 2). Be- injury (ALI) following the inhalation of gastric contents cause gastric fluid is highly acidic, it is considered that gastric as- G and is associated with significant morbidity and mor- piration triggers sterile inflammation and injury in the lung. tality (1, 2). Aspiration pneumonitis commonly occurs as a com- Recent evidence indicates that sterile inflammation is mediated by guest on September 23, 2021 plication of general anesthesia and in patients with altered levels of through the nucleotide-binding oligomerization domain-like re- consciousness due to trauma, cerebral vascular ischemia, or meta- ceptor (NLR) family pyrin domain containing 3 (NLRP3) inflam- bolic encephalopathies. The inhalation of highly acidic gastric fluid masome, an intracellular, large, multiple-protein complex that and/or particulate food matter promotes chemical pneumonitis and regulates the processing of a potent proinflammatory cytokine IL-1b the development of ALI, which can frequently be complicated by (5, 6). NLRP3 inflammasome contains NLRP3, an adaptor mole- subsequent bacterial pneumonia. Previous studies have demon- cule apoptosis-associated, speck-like protein containing a caspase strated that aspirated acid induces dysfunction of alveolar epithelial recruitment domain (ASC), and cysteine protease caspase-1, which fluid transport, followed by alveolar epithelial cell injury and neu- induces caspase-1 activation. Because caspase-1 is known to be an trophil infiltration in the lung (3, 4). However, the mechanisms that IL-1b–converting enzyme (7), its activation processes pro–IL-1b underline acid aspiration–induced ALI are unclear, because acid into its mature form and induces IL-1b production, thereby lead- itself is rapidly neutralized by proteins and bicarbonate systems (4). ing to an inflammatory response and tissue injury. Indeed, we re- Recent investigations have shown that inflammation plays a pivotal cently demonstrated that NLRP3 inflammasome was involved in the *Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical performed liquid chromatography–tandem mass spectrometry and analyzed the data. University, Shimotsuke, Tochigi 329-0498, Japan; †Division of Pulmonary Medicine, N.M., T. Kasahara, S.K., M.B., and K.H. discussed the data and provided scientific Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498, advice. Y.M. and M.T. wrote the manuscript. Japan; ‡Department of Pulmonary Medicine, Jichi Medical University, Saitama Medical x Address correspondence and reprint requests to Prof. Masafumi Takahashi, Division of Center, Saitama 330-8503, Japan; and Division of Clinical Pharmacology, Department Inflammation Research, Center for Molecular Medicine, Jichi Medical University, 3311-1 of Pharmacology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. E-mail address: [email protected] ORCIDs: 0000-0002-7441-0382 (H.K.); 0000-0002-6110-9603 (S.W.); 0000-0001- Abbreviations used in this article: AEBSF, 4-(2-aminoethyl)benzenesulfonyl 6970-9657 (R.K.); 0000-0003-3360-3185 (T. Komada); 0000-0001-7687- fluoride hydrochloride; ALI, acute lung injury; BALF, bronchoalveolar lavage 5477 (T. Kasahara); 0000-0003-2716-7532 (M.T.). fluid; CGI, cathepsin G inhibitor I; HCl, hydrochloric acid; 4-HNE, 4-hydroxy- Received for publication February 8, 2019. Accepted for publication April 17, 2019. 2-nonenal; IL-1Ra, IL-1R antagonist; NLR, nucleotide-binding oligomerization domain-like receptor; NLRP3, NLR family pyrin domain containing 3; ROS, This work was supported by grants from the Japan Society for the Promotion of Science reactive oxygen species; sgRNA, single-guide RNA; UBSS, unbuffered balanced through Grants-in-Aid for Scientific Research 16H07151 (to Y.M.) and 18K08112 (to M.T.), salt solution; WT, wild-type. the Private University Research Branding Project (to M.T.), the Agency for Medical Research and Development-Core Research for Evolutional Science and Technology Ó (18gm0610012h0105 to M.T.), the Takeda Science Foundation (to M.T.), and a Jichi Medical Copyright 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 University Graduate Student Start-Up Award and Student Research Award (to Y.M.). Y.M. and M.T. designed the study concept and experiments. Y.M., T. Karasawa, H.K., S.W., R.K., and T. Komada performed the experiments and analyzed the data. K.A. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900168 2 IL-1b PROCESSING IN ACID-INDUCED INFLAMMATION pathogenesis of sterile inflammation-related diseases (8–12). In using a Takara TP960 PCR Thermal Cycler Dice Real Time System terms of acidic stress, a mild acidic environment (pH 6–6.5) (Takara Bio, Shiga, Japan) to detect mRNA. The primers (antisense and 9 frequently occurs at sites of inflammation and ischemia (13, 14). sense, respectively) were as follows: Il1b:5-TGAAGTTGACGGACCC- CAAA-39 and 59-TGATGTGCTGCTGTGAGATT-39, Ccl2:59-GGCTCAG- Several studies have suggested that an inflammatory response is CCAGATGCAGTTAAC-39 and 59-GCCTACTCATTGGGATCATCTTG-39, influenced under mild acidic conditions. However, the role of Cxcl1:59-GCTGGGATTCACCTCAAGAA-39 and 59-TCTCCGTTACTTG- NLRP3 inflammasome under such mild acidic conditions re- GGGACAC-39,18SrRNA(Rn18s): 59-GTAACCCGTTGAACCCCATT-39 9 9 9 mains controversial. For instance, Rajamaki et al. (15) recently and 5 -CCATCCAATCGGTAGTAGCG-3 , CCL2:5-CAGCCAGATGCA- ATCAATGCC-39and 59-TGGAATCCTGAACCCACTTCT-39,CXCL1:59-GGAAC- demonstrated that mild acidic stress triggered NLRP3 inflam- AGAAGAGGAAAGAGAGAC-39 and 59-TAGGACAGTGTGCAGGTAGA-39, + masome activation and IL-1b production through K efflux in and 18S rRNA (RNA18S5): 59-GTAACCCGTTGAACCCCATT-39
Load more

Recommended publications
  • Scholarly Commons NLRX1 Modulates Differentially NLRP3
    University of the Pacific Scholarly Commons Dugoni School of Dentistry Faculty Articles Arthur A. Dugoni School of Dentistry 10-1-2018 NLRX1 modulates differentially NLRP3 inflammasome activation and NF-κB signaling during Fusobacterium nucleatum infection Shu Chen Hung University of the Pacific Arthur A. Dugoni School of Dentistry Pei Rong Huang Chang Gung University Cassio Luiz Coutinho Almeida-Da-Silva University of the Pacific Arthur A. Dugoni School of Dentistry, [email protected] Kalina R. Atanasova University of Florida Ozlem Yilmaz Medical University of South Carolina See next page for additional authors Follow this and additional works at: https://scholarlycommons.pacific.edu/dugoni-facarticles Part of the Dentistry Commons Recommended Citation Hung, S., Huang, P., Almeida-Da-Silva, C. L., Atanasova, K. R., Yilmaz, O., & Ojcius, D. M. (2018). NLRX1 modulates differentially NLRP3 inflammasome activation and NF-κB signaling during Fusobacterium nucleatum infection. Microbes and Infection, 20(9-10), 615–625. DOI: 10.1016/j.micinf.2017.09.014 https://scholarlycommons.pacific.edu/dugoni-facarticles/705 This Article is brought to you for free and open access by the Arthur A. Dugoni School of Dentistry at Scholarly Commons. It has been accepted for inclusion in Dugoni School of Dentistry Faculty Articles by an authorized administrator of Scholarly Commons. For more information, please contact [email protected]. Authors Shu Chen Hung, Pei Rong Huang, Cassio Luiz Coutinho Almeida-Da-Silva, Kalina R. Atanasova, Ozlem Yilmaz, and David M. Ojcius This article is available at Scholarly Commons: https://scholarlycommons.pacific.edu/dugoni-facarticles/705 Version of Record: https://www.sciencedirect.com/science/article/pii/S1286457917301582 Manuscript_dd7f93413c97aff4865d54242a8b21e7 1 NLRX1 modulates differentially NLRP3 inflammasome activation 2 and NF-κB signaling during Fusobacterium nucleatum infection 3 4 5 Shu-Chen Hung 1, *, Pei-Rong Huang 2, Cássio Luiz Coutinho Almeida-da-Silva 1,3 , 6 Kalina R.
    [Show full text]
  • ATP-Binding and Hydrolysis in Inflammasome Activation
    molecules Review ATP-Binding and Hydrolysis in Inflammasome Activation Christina F. Sandall, Bjoern K. Ziehr and Justin A. MacDonald * Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada; [email protected] (C.F.S.); [email protected] (B.K.Z.) * Correspondence: [email protected]; Tel.: +1-403-210-8433 Academic Editor: Massimo Bertinaria Received: 15 September 2020; Accepted: 3 October 2020; Published: 7 October 2020 Abstract: The prototypical model for NOD-like receptor (NLR) inflammasome assembly includes nucleotide-dependent activation of the NLR downstream of pathogen- or danger-associated molecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomeric platforms that lie upstream of inflammatory responses associated with innate immunity. As members of the STAND ATPases, the NLRs are generally thought to share a similar model of ATP-dependent activation and effect. However, recent observations have challenged this paradigm to reveal novel and complex biochemical processes to discern NLRs from other STAND proteins. In this review, we highlight past findings that identify the regulatory importance of conserved ATP-binding and hydrolysis motifs within the nucleotide-binding NACHT domain of NLRs and explore recent breakthroughs that generate connections between NLR protein structure and function. Indeed, newly deposited NLR structures for NLRC4 and NLRP3 have provided unique perspectives on the ATP-dependency of inflammasome activation. Novel molecular dynamic simulations of NLRP3 examined the active site of ADP- and ATP-bound models. The findings support distinctions in nucleotide-binding domain topology with occupancy of ATP or ADP that are in turn disseminated on to the global protein structure.
    [Show full text]
  • Coincidental Loss of DOCK8 Function in NLRP10-Deficient and C3H/Hej Mice Results in Defective Dendritic Cell Migration
    Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration Jayendra Kumar Krishnaswamya,b,1, Arpita Singha,b,1, Uthaman Gowthamana,b, Renee Wua,b, Pavane Gorrepatia,b, Manuela Sales Nascimentoa,b, Antonia Gallmana,b, Dong Liua,b, Anne Marie Rhebergenb, Samuele Calabroa,b, Lan Xua,b, Patricia Ranneya,b, Anuj Srivastavac, Matthew Ransond, James D. Gorhamd, Zachary McCawe, Steven R. Kleebergere, Leonhard X. Heinzf, André C. Müllerf, Keiryn L. Bennettf, Giulio Superti-Furgaf, Jorge Henao-Mejiag, Fayyaz S. Sutterwalah, Adam Williamsi, Richard A. Flavellb,j,2, and Stephanie C. Eisenbartha,b,2 Departments of aLaboratory Medicine and bImmunobiology and jHoward Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520; cComputational Sciences, The Jackson Laboratory, Bar Harbor, ME 04609; dDepartment of Pathology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755; eNational Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; fCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; gInstitute for Immunology, Departments of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; hInflammation Program, Department of Internal Medicine, University of Iowa, Iowa City, IA 52241; and iThe Jackson Laboratory for Genomic Medicine, Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT 06032 Contributed by Richard A. Flavell, January 28, 2015 (sent for review December 23, 2014; reviewed by Matthew L. Albert and Thirumala-Devi Kanneganti) Dendritic cells (DCs) are the primary leukocytes responsible for NLRP10 is the only NOD-like receptor (NLR) without a leu- priming T cells.
    [Show full text]
  • A Role for the Nlr Family Members Nlrc4 and Nlrp3 in Astrocytic Inflammasome Activation and Astrogliosis
    A ROLE FOR THE NLR FAMILY MEMBERS NLRC4 AND NLRP3 IN ASTROCYTIC INFLAMMASOME ACTIVATION AND ASTROGLIOSIS Leslie C. Freeman A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Genetics and Molecular Biology. Chapel Hill 2016 Approved by: Jenny P. Y. Ting Glenn K. Matsushima Beverly H. Koller Silva S. Markovic-Plese Pauline. Kay Lund ©2016 Leslie C. Freeman ALL RIGHTS RESERVED ii ABSTRACT Leslie C. Freeman: A Role for the NLR Family Members NLRC4 and NLRP3 in Astrocytic Inflammasome Activation and Astrogliosis (Under the direction of Jenny P.Y. Ting) The inflammasome is implicated in many inflammatory diseases but has been primarily studied in the macrophage-myeloid lineage. Here we demonstrate a physiologic role for nucleotide-binding domain, leucine-rich repeat, CARD domain containing 4 (NLRC4) in brain astrocytes. NLRC4 has been primarily studied in the context of gram-negative bacteria, where it is required for the maturation of pro-caspase-1 to active caspase-1. We show the heightened expression of NLRC4 protein in astrocytes in a cuprizone model of neuroinflammation and demyelination as well as human multiple sclerotic brains. Similar to macrophages, NLRC4 in astrocytes is required for inflammasome activation by its known agonist, flagellin. However, NLRC4 in astrocytes also mediate inflammasome activation in response to lysophosphatidylcholine (LPC), an inflammatory molecule associated with neurologic disorders. In addition to NLRC4, astrocytic NLRP3 is required for inflammasome activation by LPC. Two biochemical assays show the interaction of NLRC4 with NLRP3, suggesting the possibility of a NLRC4-NLRP3 co-inflammasome.
    [Show full text]
  • Criteria for CAPS, Is It All in the Name? Markers, Urticaria-Like Rash and Arthralgia) Would Perform Well with These Four FCAS, but Only FCAS1 Is a CAPS
    ARD Online First, published on November 16, 2016 as 10.1136/annrheumdis-2016-210681 Ann Rheum Dis: first published as 10.1136/annrheumdis-2016-210681 on 16 November 2016. Downloaded from Correspondence Criteria for CAPS, is it all in the name? markers, urticaria-like rash and arthralgia) would perform well with these four FCAS, but only FCAS1 is a CAPS. The authors ‘ This paper1 describes an original work conducted by an fairly admitted that the number of CAPS cases and controls was International team of 16 recognised clinical experts in the field limited and not all possible differential diagnoses of CAPS may of autoinflammatory diseases. The aim of this consortium was have been included, potentially leading to an overestimation of fi ’ to develop diagnostic criteria for cryopyrin-associated periodic the speci city of the proposed model . fl syndrome (CAPS). They resulted in a model that indisputably is The issue of the disease name, re ecting either the main relevant to describe these rare and heterogeneous diseases symptoms or the molecular mechanisms of the condition, has fl among other autoinflammatory diseases. Their proposed CAPS been raised many times in the autoin ammatory diseases com- fi diagnosis criteria are primarily clinical. munity, and propositions for re ned taxonomy will shortly We would like to comment on the pathophysiological mech- emerge. The debate is not just semantic as differential thera- anism underlying ‘CAPS’. The NLRP3 gene encodes cryopyrin, peutic approaches can be taken according to the molecular the historical name of the NLRP3 protein, a key component of defect in cause in the condition presented by the patient.
    [Show full text]
  • NAIP5/NLRC4 Inflammasomes Compounds Inhibit the NLRP1, NLRP3, and Arsenic Trioxide and Other Arsenical
    The Journal of Immunology Arsenic Trioxide and Other Arsenical Compounds Inhibit the NLRP1, NLRP3, and NAIP5/NLRC4 Inflammasomes Nolan K. Maier,* Devorah Crown,* Jie Liu,† Stephen H. Leppla,* and Mahtab Moayeri* Inflammasomes are large cytoplasmic multiprotein complexes that activate caspase-1 in response to diverse intracellular danger signals. Inflammasome components termed nucleotide-binding oligomerization domain–like receptor (NLR) proteins act as sensors for pathogen-associated molecular patterns, stress, or danger stimuli. We discovered that arsenicals, including arsenic trioxide and sodium arsenite, inhibited activation of the NLRP1, NLRP3, and NAIP5/NLRC4 inflammasomes by their respective activat- ing signals, anthrax lethal toxin, nigericin, and flagellin. These compounds prevented the autoproteolytic activation of caspase-1 and the processing and secretion of IL-1b from macrophages. Inhibition was independent of protein synthesis induction, proteasome-mediated protein breakdown, or kinase signaling pathways. Arsenic trioxide and sodium arsenite did not directly modify or inhibit the activity of preactivated recombinant caspase-1. Rather, they induced a cellular state inhibitory to both the autoproteolytic and substrate cleavage activities of caspase-1, which was reversed by the reactive oxygen species scavenger N-acetylcysteine but not by reducing agents or NO pathway inhibitors. Arsenicals provided protection against NLRP1-dependent anthrax lethal toxin–mediated cell death and prevented NLRP3-dependent neutrophil recruitment in a monosodium urate crystal inflammatory murine peritonitis model. These findings suggest a novel role in inhibition of the innate immune response for arsenical compounds that have been used as therapeutics for a few hundred years. The Journal of Immunology, 2014, 192: 763–770. nflammasomes are large cytoplasmic multiprotein complexes domain–containing protein 4 (NLRC4) inflammasome by direct that form in response to intracellular danger signals.
    [Show full text]
  • A Small-Molecule Inhibitor of the NLRP3 Inflammasome for the Treatment of Inflammatory Diseases
    ARTICLES A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases Rebecca C Coll1,2, Avril A B Robertson2, Jae Jin Chae3, Sarah C Higgins1, Raúl Muñoz-Planillo4, Marco C Inserra2,5, Irina Vetter2,5, Lara S Dungan1, Brian G Monks6, Andrea Stutz6, Daniel E Croker2, Mark S Butler2, Moritz Haneklaus1, Caroline E Sutton1, Gabriel Núñez4, Eicke Latz6–8, Daniel L Kastner3, Kingston H G Mills1, Seth L Masters9, Kate Schroder2, Matthew A Cooper2 & Luke A J O’Neill1 The NOD-like receptor (NLR) family, pyrin domain–containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer’s disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1b (IL-1b) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle–Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease. The NLR family protein NLRP3 is an intracellular signaling molecule A role for NLRP3 in diseases of the central nervous system is that senses many pathogen-derived, environmental and host-derived emerging, and lung diseases have also been shown to be influenced factors1.
    [Show full text]
  • Development of a Characterised Tool Kit for the Interrogation of NLRP3
    www.nature.com/scientificreports OPEN Development of a characterised tool kit for the interrogation of NLRP3 infammasome-dependent Received: 19 January 2018 Accepted: 21 March 2018 responses Published: xx xx xxxx Elena Redondo-Castro1, Dorte Faust2, Simon Fox2, Alex G. Baldwin 3, Simon Osborne2, Michael J. Haley 1, Eric Karran4, Hugh Nuthall5, Peter J. Atkinson6, Lee A. Dawson7, Carol Routledge8, Stuart M. Allan1, Sally Freeman3, Janet Brownlees2 & David Brough 1 Infammation is an established contributor to disease and the NLRP3 infammasome is emerging as a potential therapeutic target. A number of small molecule inhibitors of the NLRP3 pathway have been described. Here we analysed the most promising of these inhibitor classes side by side to assess relative potency and selectivity for their respective putative targets. Assessed using ASC infammasome-speck formation, and release of IL-1β, in both human monocyte/macrophage THP1 cells and in primary mouse microglia, we compared the relative potency and selectivity of P2X7 inhibitors, infammasome inhibitors (diarylsulfonylurea vs. the NBC series), and caspase-1 inhibitors. In doing so we are now able to provide a well characterised small molecule tool kit for interrogating and validating infammasome- dependent responses with a range of nanomolar potency inhibitors against established points in the infammasome pathway. Infammation is a protective host response to infection, but when it occurs during non-communicable dis- ease it is ofen damaging and contributes to an acceleration of pathology and a worse outcome. An important infammatory process in disease is the activation of a multi-molecular complex called the NLRP3 infammasome (Fig. 1)1. Te NLRP3 infammasome consists of a pattern recognition receptor (PRR), which in this case is NLRP3 (NOD-like receptor (NLR) family, pyrin domain–containing protein 3 (NLRP3)), an adaptor protein called ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (CARD)), and pro-caspase-12.
    [Show full text]
  • NOD-Like Receptors (Nlrs) and Inflammasomes
    International Edition www.adipogen.com NOD-like Receptors (NLRs) and Inflammasomes In mammals, germ-line encoded pattern recognition receptors (PRRs) detect the presence of pathogens through recognition of pathogen-associated molecular patterns (PAMPs) or endogenous danger signals through the sensing of danger-associated molecular patterns (DAMPs). The innate immune system comprises several classes of PRRs that allow the early detection of pathogens at the site of infection. The membrane-bound toll-like receptors (TLRs) and C-type lectin receptors (CTRs) detect PAMPs in extracellular milieu and endo- somal compartments. TRLs and CTRs cooperate with PRRs sensing the presence of cytosolic nucleic acids, like RNA-sensing RIG-I (retinoic acid-inducible gene I)-like receptors (RLRs; RLHs) or DNA-sensing AIM2, among others. Another set of intracellular sensing PRRs are the NOD-like receptors (NLRs; nucleotide-binding domain leucine-rich repeat containing receptors), which not only recognize PAMPs but also DAMPs. PAMPs FUNGI/PROTOZOA BACTERIA VIRUSES MOLECULES C. albicans A. hydrophila Adenovirus Bacillus anthracis lethal Plasmodium B. brevis Encephalomyo- toxin (LeTx) S. cerevisiae E. coli carditis virus Bacterial pore-forming L. monocytogenes Herpes simplex virus toxins L. pneumophila Influenza virus Cytosolic dsDNA N. gonorrhoeae Sendai virus P. aeruginosa Cytosolic flagellin S. aureus MDP S. flexneri meso-DAP S. hygroscopicus S. typhimurium DAMPs MOLECULES PARTICLES OTHERS DNA Uric acid UVB Extracellular ATP CPPD Mutations R837 Asbestos Cytosolic dsDNA Irritants Silica Glucose Alum Hyaluronan Amyloid-b Hemozoin Nanoparticles FIGURE 1: Overview on PAMPs and DAMPs recognized by NLRs. NOD-like Receptors [NLRs] The intracellular NLRs organize signaling complexes such as inflammasomes and NOD signalosomes.
    [Show full text]
  • Sensing Soluble Uric Acid by Naip1-Nlrp3 Platform
    bioRxiv preprint doi: https://doi.org/10.1101/2020.05.15.077644; this version posted May 15, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Sensing soluble uric acid by Naip1-Nlrp3 platform Tarcio Teodoro Braga1,2,3, Mariana Rodrigues Davanso2,3,4, Davi Mendes5, Tiago Antonio de Souza5, Anderson Fernandes de Brito6, Mario Costa Cruz2, Meire Ioshie Hiyane2, Dhemerson Souza de Lima2, Vinicius Nunes2, Juliana de Fátima Giarola7, Denio Emanuel Pires Souto7,8, Tomasz Próchnicki3, Mario Lauterbach3, Stellee Marcela Petris Biscaia9, Rilton Alves de Freitas8, Rui Curi4,10, Alessandra Pontillo2, Eicke Latz3,11,12,*, Niels Olsen Saraiva Camara2,13, 14,* 1. Department of Basic Pathology, Federal University of Parana, Curitiba, PR, Brazil 2. Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, SP, Brazil 3. Institute of Innate Immunity, University Hospitals Bonn, Bonn, Germany 4. Department of Physiology and Biophysics, Institute of Biomedical Sciences I, University of Sao Paulo, SP, Brazil 5. Department of Microbiology, Institute of Biomedical Sciences II, University of São Paulo, SP, Brazil 6. Department of Life Sciences, Imperial College London, London, SW7 2AZ 7. Institute of Chemistry, University of Campinas, Campinas, SP, Brazil 8. Department of Chemistry, Federal University of Parana, Curitiba, PR, Brazil 9. Department of Cellular Biology, Federal University of Parana, Curitiba, PR, Brazil 10. Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil 11. Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA 12.
    [Show full text]
  • Salmonella Flagellin Activates NAIP/NLRC4 and Canonical NLRP3 Inflammasomes in Human Macrophages
    Salmonella Flagellin Activates NAIP/NLRC4 and Canonical NLRP3 Inflammasomes in Human Macrophages This information is current as Anna M. Gram, John A. Wright, Robert J. Pickering, of September 28, 2021. Nathaniel L. Lam, Lee M. Booty, Steve J. Webster and Clare E. Bryant J Immunol published online 30 December 2020 http://www.jimmunol.org/content/early/2020/12/29/jimmun ol.2000382 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2020/12/29/jimmunol.200038 Material 2.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Author Choice Freely available online through The Journal of Immunology Author Choice option Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 The Authors All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published December 30, 2020, doi:10.4049/jimmunol.2000382 The Journal of Immunology Salmonella Flagellin Activates NAIP/NLRC4 and Canonical NLRP3 Inflammasomes in Human Macrophages Anna M. Gram,* John A. Wright,*,1 Robert J. Pickering,* Nathaniel L. Lam,*,† Lee M.
    [Show full text]
  • Full Text in Diva
    http://www.diva-portal.org This is the published version of a paper published in Mediators of Inflammation. Citation for the original published paper (version of record): Hedbrant, A., Andersson, L., Bryngelsson, I-L., Eklund, D., Westberg, H. et al. (2020) Quartz Dust Exposure Affects NLRP3 Inflammasome Activation and Plasma Levels of IL-18 and IL-1Ra in Iron Foundry Workers Mediators of Inflammation, : 8490908 https://doi.org/10.1155/2020/8490908 Access to the published version may require subscription. N.B. When citing this work, cite the original published paper. Permanent link to this version: http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-79441 Hindawi Mediators of Inflammation Volume 2020, Article ID 8490908, 10 pages https://doi.org/10.1155/2020/8490908 Research Article Quartz Dust Exposure Affects NLRP3 Inflammasome Activation and Plasma Levels of IL-18 and IL-1Ra in Iron Foundry Workers Alexander Hedbrant ,1,2 Lena Andersson,3 Ing-Liss Bryngelsson,3 Daniel Eklund ,1,2 Håkan Westberg,1,2,3 Eva Särndahl ,1,2 and Alexander Persson 1,2 1Department of Medical Sciences, School of Medicine and Health, Örebro University, SE-701 82 Örebro, Sweden 2Inflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, SE-701 82 Örebro, Sweden 3Department of Occupational and Environmental Medicine, Örebro University Hospital, SE-701 85 Örebro, Sweden Correspondence should be addressed to Alexander Hedbrant; [email protected] Received 23 September 2019; Accepted 21 December 2019; Published 7 January 2020 Academic Editor: Daniela Novick Copyright © 2020 Alexander Hedbrant et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
    [Show full text]