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Ischemia-Reperfusion Injury Epithelial-Expressed Nlrp3 in Renal An An Inflammasome-Independent Role for Epithelial-Expressed Nlrp3 in Renal Ischemia-Reperfusion Injury This information is current as Alana A. Shigeoka, James L. Mueller, Amanpreet Kambo, of September 30, 2021. John C. Mathison, Andrew J. King, Wesley F. Hall, Jean da Silva Correia, Richard J. Ulevitch, Hal M. Hoffman and Dianne B. McKay J Immunol 2010; 185:6277-6285; Prepublished online 20 October 2010; Downloaded from doi: 10.4049/jimmunol.1002330 http://www.jimmunol.org/content/185/10/6277 References This article cites 62 articles, 15 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/185/10/6277.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 30, 2021 • Fast Publication! 4 weeks from acceptance to publication *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 Errata An erratum has been published regarding this article. Please see next page or: /content/186/3/1880.full.pdf 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 © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology An Inflammasome-Independent Role for Epithelial-Expressed Nlrp3 in Renal Ischemia-Reperfusion Injury Alana A. Shigeoka,* James L. Mueller,†,‡,x Amanpreet Kambo,* John C. Mathison,* Andrew J. King,{ Wesley F. Hall,‖ Jean da Silva Correia,* Richard J. Ulevitch,* Hal M. Hoffman,†,‡,x and Dianne B. McKay* Cytoplasmic innate immune receptors are important therapeutic targets for diseases associated with overproduction of proinflam- matory cytokines. One cytoplasmic receptor complex, the Nlrp3 inflammasome, responds to an extensive array of molecules as- sociated with cellular stress. Under normal conditions, Nlrp3 is autorepressed, but in the presence of its ligands, it oligomerizes, recruits apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc), and triggers caspase 1 activation and the maturation of proinflammatory cytokines such as IL-1b and IL-18. Because ischemic tissue injury provides a potential source for Nlrp3 ligands, our study compared and contrasted the effects of renal ischemia in wild-type mice and mice deficient in Downloaded from components of the Nlrp3 inflammasome (Nlrp32/2 and Asc2/2 mice). To examine the role of the inflammasome in renal ischemia- reperfusion injury (IRI) we also tested its downstream targets caspase 1, IL-1b, and IL-18. Both Nlrp3 and Asc were highly expressed in renal tubular epithelium of humans and mice, and the absence of Nlrp3, but not Asc or the downstream inflamma- some targets, dramatically protected from kidney IRI. We conclude that Nlrp3 contributes to renal IRI by a direct effect on renal tubular epithelium and that this effect is independent of inflammasome-induced proinflammatory cytokine production. The Journal of Immunology, 2010, 185: 6277–6285. http://www.jimmunol.org/ remendous interest has evolved over the past decade in Naip, CIITA, HET-E, and telomerase-associated protein 1 domain, innate immune sensing receptors and their role in disease and several leucine-rich repeats at the C-terminal end (2). One of the T processes. Of the known innate immune receptors, the best best-described members of the NLR family is Nlrp3 (also called described are the membrane-bound TLRs; many recent discoveries cyropyrin, CIAS1, or Nalp3) (3). Nlrp3 is an essential component have highlighted their importance in human diseases. Another of the caspase 1 inflammasome, a multiprotein molecular scaffold family of intracellular innate sensors, called the nucleotide-binding necessary for caspase 1 activation (4). Upon ligand sensing, Nlrp3 oligomerization domain-like receptors (NLRs), has attracted fo- recruits the adaptor protein apoptosis-associated speck-like protein by guest on September 30, 2021 cused interest as potential therapeutic targets for diseases associ- containing a caspase recruitment domain (CARD) (Asc) through ated with the overproduction of proinflammatory cytokines. The a PYD–PYD interaction. Asc then recruits inflammatory caspases NLRs are critical signaling molecules that contribute to formation (e.g., caspase 1) to the assembly complex through CARD–CARD of intracellular macromolecular complexes and regulate host im- interactions (5). The assembly complex brings into close proximity mune responses to a variety of stimuli, including pathogens, mol- the inflammatory caspases, leading to their activation (6). Activa- ecules released from injured tissue, and a variety of nonspecific tion of caspase 1 is required for processing and release of active molecules, including immune adjuvants (1). proinflammatory cytokines such as IL-1b and IL-18. The NLR family includes several different groups of intracellular A large variety of structurally unrelated stimuli activate Nlrp3, molecules sharing a N-terminal pyrin domain (PYD), a central such as microbial RNA and the imidazoquinoline compounds R837 and R848, muramyl dipeptide, polyinosinic-polycytidylic *Department of Immunology and Microbial Sciences, The Scripps Research In- acid, ATP, potassium efflux, asbestos, silica, aluminum hydroxide, stitute; {Division of Nephrology, Department of Medicine and ‖Department of Pa- amyloid b peptide, pore-forming toxins, cellular components re- thology, Scripps Clinic and Green Hospital, La Jolla, CA 92037; and †Department of x leased into the extracellular milieu by distressed cells (including Pediatrics, ‡Department of Medicine, and Ludwig Institute of Cancer Research, School of Medicine, University of California at San Diego, La Jolla, CA 92093 monosodium urate and calcium pyrophosphate dihydrate crystals Received for publication July 12, 2010. Accepted for publication September 8, 2010. found in gout and pseudogout), and cholesterol crystals (7–11). The This work was supported by National Institutes of Health Grant 1R01DK60151, fact that so many different stimuli trigger activation of Nlrp3, and Scripps Translational Science Institute Pilot Grant 1UL1RR025774 (to D.B.M.), subsequent inflammasome formation, suggests that Nlrp3 is a com- and a Renal Research Collaborative/Price Charities grant (to A.J.K.). mon hub for many different cellular triggers that lead to overpro- Address correspondence and reprint requests to Dr. Dianne McKay, Department of duction of proinflammatory cytokines. Immunology and Microbial Sciences, IMM-16, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: dmckay@ Several human diseases have been linked to Nlpr3. For instance, scripps.edu mutations in the Nlrp3 gene cause familial cold autoinflammatory Abbreviations used in this paper: Asc, apoptosis-associated speck-like protein con- syndrome, Muckle-Wells syndrome, and neonatal-onset multisys- taining a caspase recruitment domain; CARD, caspase recruitment domain; HEK, tem inflammatory disease, which are collectively known as cry- HEK 293 cells; hRTE, human RTE cells extracted from normal human kidneys; IRI, ischemia-reperfusion injury; LN, lymph node; NLR, nucleotide-binding oligomeri- opyrinopathies (3, 12–14). More recently, inflammation associated zation domain-like receptor; pre, preinjury; PYD, pyrin domain; RTE, renal tubular with gout has been linked to Nlrp3 and overproduction of IL-1b epithelium; sham, sham-operated; Thp1, Thp1 cells; WT, wild-type; WTLN, lymph (10). A central role for overproduction of IL-1b in the pathogenesis node cells from wild-type mice. of Nlrp3-related diseases has been identified by the successful Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 treatment of these diseases with IL-1–targeted therapies. The rIL- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1002330 6278 INFLAMMASOME-INDEPENDENT ROLE FOR Nlrp3 IN RENAL IRI 1R antagonist anakinra has shown remarkable therapeutic efficacy Jolla, CA). Immediately postnephrectomy, the renal pathologist removed for patients with cryopyrinopathies as well as gout (15–20). a wedge section of normal tissue (distal from the site of tumor). After Another of the disease processes linked to innate immune re- transport to the laboratory in sterile media, the renal capsule was removed and cortex dissected from the medulla. The cortex was then finely minced, ceptors is ischemic kidney injury. Ischemic kidney injury occurs placed in collagenase A (Sigma-Aldrich, St. Louis, MO), and incubated at commonly in hospitalized patients and is a complex pathophysio- 37˚C for 30 min with frequent shaking. Postincubation, the digested mixture logical process contributed to by both cell death and inflammation. was differentially sieved (200–50 mm) and washed three times with fresh Although recent attention has highlighted the important role for media. The sieved contents were then centrifuged, pelleted, and layered over 30% Percoll (Sigma-Aldrich). After spinning the Percoll mixture at TLRs in ischemic injury of the kidney (21, 22), as well as other 21,500 3 g for 30 min, four distinct bands were apparent as previously
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