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Cathepsin C Independent Component That Requires The IL-1−Dependent Sterile Inflammatory Response Has a Substantial Caspase-1− Independent Component That Requires Cathepsin C This information is current as of September 23, 2021. Hajime Kono, Gregory M. Orlowski, Zubin Patel and Kenneth L. Rock J Immunol published online 22 August 2012 http://www.jimmunol.org/content/early/2012/08/22/jimmun ol.1200136 Downloaded from Why The JI? Submit online. http://www.jimmunol.org/ • 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 *average by guest on September 23, 2021 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 © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published August 22, 2012, doi:10.4049/jimmunol.1200136 The Journal of Immunology The IL-1–Dependent Sterile Inflammatory Response Has a Substantial Caspase-1–Independent Component That Requires Cathepsin C Hajime Kono,* Gregory M. Orlowski,† Zubin Patel,† and Kenneth L. Rock† The sterile inflammatory response to cell death and irritant crystals is medically important because it causes disease. Although these stimuli are structurally distinct, they cause inflammation through a common pathway that requires the cytokine IL-1. In vitro, the inflammasome, and in particular its generation of active caspase-1, is absolutely required to produce bioactive IL-1b. However, in this study, we report that caspase-1 is not required in vivo for much of the IL-1b–dependent sterile inflammatory response. Furthermore, we find that cathepsin C, which controls the activity of a number of leukocyte serine proteases capable of processing IL-1b, plays a major role in this caspase-1–independent pathway. Mice that are deficient in cathepsin C have reduced inflam- Downloaded from matory responses to dying cells and silica crystals. In the absence of cathepsin C, caspase-1 becomes rate limiting such that mice doubly deficient in both of these proteases make little IL-1b in vivo and have markedly attenuated inflammatory responses to the sterile stimuli. In contrast, these mutant mice generate normal inflammation in response to exogenous IL-1b, indicating that cathepsin C and caspase-1 function upstream of IL-1b, and, in their absence, all components of the pathway downstream of mature IL-1b are intact. The Journal of Immunology, 2012, 189: 000–000. http://www.jimmunol.org/ ell death and a number of irritant particles, such as sili- a key role for IL-1b in responses to these particles has not been cates, calcium pyrophosphate, and urate, stimulate robust formally shown in vivo (6). C inflammatory responses in vivo and, as a result, can cause IL-1b is initially transcribed and translated into a proform that or exacerbate tissue damage and disease (1). Recently, it has been is biologically inactive (5). The generation of mature and active recognized that these diverse stimuli all elicit inflammation IL-1b requires proteolytic removal of a propeptide sequence from through a common pathway. These sterile inflammatory responses the cytokine precursor. This proteolytic processing of pro–IL-1b all require the IL-1R and its signaling adaptor molecules (2). in cells is controlled by a macromolecular complex, called the Moreover, where examined, IL-1 blocking reagents also inhibit inflammasome (7–11). This structure forms upon the oligomeri- these responses (3, 4). Therefore, it is now established that the zation of three distinct components. One subunit is a nucleotide- by guest on September 23, 2021 cytokine IL-1 plays an essential role in these sterile inflammatory binding domain, leucine-rich–containing (NLR) family protein responses. There are two distinct forms of IL-1, IL-1a and IL-1b, that is thought to control the activity of the complex; for many and both of these cytokines work through the same receptor, IL- sterile particulates, the NLR protein is NLRP3. A second com- 1R1 (5). It has generally been assumed that proinflammatory ponent is the apoptosis-associated speck-like protein containing particles cause inflammation by stimulating the production of IL- a caspase-recruitment domain subunit, which is thought to serve 1b, and, indeed, in vitro they stimulate macrophages to produce as a scaffold that allows the complex to oligomerize. The third this cytokine; however, IL-1a is also produced, and, in most cases, component is procaspase-1, which is the inactive precursor of the protease caspase-1. When the NLRP3 inflammasome is stimu- lated, procaspase is cleaved to its active form, and this in turn cleaves pro–IL-1b to mature IL-1b. The mature cytokine is then *Department of Internal Medicine, Teikyo University School of Medicine, Tokyo 173-8605, Japan; and †Department of Pathology, University of Massachusetts Med- released from cells via a nonclassical secretion pathway, and this ical School, Worcester, MA 01655 process may also be controlled by the inflammasome. Received for publication January 13, 2012. Accepted for publication July 25, 2012. The inflammasome has been shown to be absolutely essential for This work was supported by grants from the National Institutes of Health (to K.L.R.), the production of IL-1b in vitro (12, 13). Macrophages that ge- and core resources supported by Diabetes Endocrinology Research Center Grant netically lack NLRP3, apoptosis-associated speck-like protein DK32520 were also used. This work was also supported by a Grant for Research on Intractable Diseases from the Ministry of Health, Labour, and Welfare and a containing a caspase-recruitment domain, or caspase-1 fail to pro- Grant-in-Aid for Scientific Research (C) and Grant-in-Aid for Scientific Research duce any mature IL-1b in response to a number of sterile stimuli, on Innovative Areas from the Ministry of Education, Culture, Sports, Science, and including crystals of silica, urate, or other particles (14, 15). Based Technology of Japan. H.K. is supported by Mochida Memorial Foundation for Med- ical and Pharmaceutical Research, Public Trust Cardiovascular Research Fund, on these results, it has generally been assumed that the inflamma- Senshin Medical Research Foundation, Kowa Life Science Foundation, Naito Foun- some similarly controls the production of IL-1b in vivo, and, in- dation, Takeda Science Foundation, and NOVARTIS Foundation (Japan) for the deed, genetic knockouts of inflammasome components do reduce Promotion of Science. G.M.O. is supported by Medical Scientist Training Program Training Grant T32 AI095213-01 from the National Institutes of Health. responses in animals in which IL-1 participates (12, 16). However, Address correspondence and reprint requests to Dr. Kenneth L. Rock, University of where examined, at least some of these responses are not com- Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. pletely eliminated in inflammasome-deficient mice (14, 16, 17), E-mail address: [email protected] although it has not been clear why. The inflammasome-independent Abbreviations used in this article: NLR, nucleotide-binding domain, leucine-rich– portion of these responses could be due to IL-1a (that doesn’t re- containing; WT, wild-type. quire caspase-1 for activity), other cytokines, or other ways of Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 producing IL-1b. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1200136 2 CATHEPSIN C IN IL-1–DEPENDENT STERILE INFLAMMATION In addition to the inflammasome pathway, there are other po- then heat shocked at 45˚C for 10 min, followed by 37˚C incubation for 5 h; tential mechanisms by which pro–IL-1b could be cleaved into this resulted in necrosis (7-aminoactinomycin D/propidium iodide-positive mature IL-1b. In vitro, a number of cellular proteases, including cells). neutrophil serine proteases (elastase, cathepsin G, and protease 3), Neutrophil and monocyte recruitment to peritoneal cavity matrix metalloproteinases, and mast cell chymase, can cleave b b Quantification of recruited neutrophils and monocytes to the peritoneal purified pro–IL-1 to bioactive IL-1 (18–21). Whether and to cavity was described before (6). Mice were injected i.p. with indicated what extent these mechanisms contribute to IL-1 production in amount of silica crystal or necrotic EL4 cells in 150 ml PBS. After 4 or various settings is unclear. There are limited data that chemical 16 h of injection, the peritoneum was lavaged with 6 ml PBS with 2% FCS, 3 mM EDTA, and 10 U/ml heparin. The absolute number of neutrophils (Ly- inhibitors of elastase and chymase could reduce the processing of + + 2 + m b 6G 7/4 ) and monocytes (Ly-6G 7/4 )in100 l lavage was counted using pro–IL-1 by neutrophils or mast cells, respectively, in vitro and a flow cytometer equipped with a high throughput sampler (BD Biosciences). reduce IL-1b levels and inflammation in vivo (22). Another neu- b trophil serine protease, protease 3, has been implicated in IL-1b– Measurement of the mature IL-1 of the peritoneal cavity dependent chronic arthritis in a streptococcal cell wall model (23). Mature IL-1b was measured using a previously described MRC-5 fibro- A limitation of studies using protease inhibitors is the potential blast bioassay (30). The peritoneal cavity of the silica-stimulated mouse that they may have pleotropic effects that can influence responses. was lavaged using 1 ml PBS. The supernatant of the lavage was treated b Overall, the role of these alternate IL-1–processing mechanisms in with anti–IL-1 or control Ab (24).
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