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Production of IL-18 Binding Protein by Radiosensitive and Radioresistant Production of IL-18 Binding Protein by Radiosensitive and Radioresistant Cells in CpG-Induced Macrophage Activation Syndrome This information is current as of October 4, 2021. Mathilde Harel, Charlotte Girard-Guyonvarc'h, Emiliana Rodriguez, Gaby Palmer and Cem Gabay J Immunol published online 10 July 2020 http://www.jimmunol.org/content/early/2020/07/09/jimmun ol.2000168 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2020/07/10/jimmunol.200016 Material 8.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 October 4, 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 © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published July 10, 2020, doi:10.4049/jimmunol.2000168 The Journal of Immunology Production of IL-18 Binding Protein by Radiosensitive and Radioresistant Cells in CpG-Induced Macrophage Activation Syndrome Mathilde Harel,*,† Charlotte Girard-Guyonvarc’h,† Emiliana Rodriguez,*,† Gaby Palmer,*,†,1 and Cem Gabay*,†,1 IL-18 binding protein (IL-18BP) acts as a naturally occurring IL-18 decoy receptor. If the balance between IL-18 and IL-18BP is dysregulated, abnormal levels of free bioactive IL-18 are detected, such as in the sera of Il-18bp knockout (KO) mice with CpG- induced macrophage activation syndrome. To determine the cellular sources of Il-18bp in vivo, we selectively depleted Il-18bp expression in either radiosensitive or radioresistant cells using bone marrow transfer between wild-type (WT) and Il-18bp KO mice. Following repeated CpG injections, Il-18bp KO (donor)→ Il-18bp KO (recipient) chimeric mice exhibited more severe disease, with an enhanced Ifn-g signature and circulating free Il-18 levels, in comparison with WT→WT chimeras. Interestingly, Downloaded from the phenotype of KO→WT and WT→KO mice did not differ from that of WT→WT mice. Consistent with this finding, serum Il- 18bp levels were similar in these three groups of mice. The contribution of radioresistant and radiosensitive cells to Il-18bp production varied markedly according to the organ examined, with a major contribution of radiosensitive cells in the spleen as opposed to a major contribution of radioresistant cells in the lung. Finally, Ifn-g blockade abrogated the CpG-induced but not the constitutive Il-18bp production. Our results demonstrate that circulating Il-18bp is induced in response to Ifn-g during CpG- induced macrophage activation syndrome and is present at high levels in the circulation to prevent the deleterious systemic effects http://www.jimmunol.org/ of Il-18. The Journal of Immunology, 2020, 205: 000–000. nterleukin-18 is a proinflammatory cytokine that belongs to when considering the pathogenic role of IL-18 in inflammatory the IL-1 family and has initially been described as an IFN-g– conditions (7–12). I inducing factor (1–6). IL-18 activity is regulated by IL-18 Hemophagocytic lymphohistiocytosis (HLH) or hemophago- binding protein (IL-18BP), a naturally occurring soluble inhibitor cytic syndromes correspond to rare, life-threatening, hyper- that makes high-affinity complexes with IL-18, thus preventing its inflammatory conditions with several causes, symptoms, and binding to its cell surface receptors. IL-18BP is present in large outcomes. Traditionally, HLH is divided into primary and sec- by guest on October 4, 2021 concentrations in the circulation. As a consequence, circulating ondary forms that share various clinical and laboratory features. In levels of unbound, free IL-18 are undetectable in healthy indi- the primary forms of HLH or familial HLH (fHLH), an impairment viduals. Furthermore, rather than total IL-18 levels, the IL-18/IL- in cytolytic activity provoked by autosomal recessive disorders 18BP balance and the concentrations of free IL-18 are relevant associated with viral infections causes the syndrome. In contrast to fHLH, the secondary form, also termed macrophage activation syndrome (MAS), is a complex disease with probable influences of multiple genes and environmental factors (13–16). MAS can occur *Department of Pathology and Immunology, School of Medicine, University of as a life-threatening complication of inflammatory diseases, such † Geneva, CH-1211 Geneva 4, Switzerland; and Division of Rheumatology, Depart- as systemic juvenile idiopathic arthritis (sJIA), as well as fol- ment of Medicine, University Hospitals, CH-1211 Geneva 14, Switzerland lowing viral infections and in patients with cancer (17). The 1G.P. and C.G. contributed equally to this work. mechanisms responsible for the pathogenesis of MAS are unclear, ORCIDs: 0000-0002-4901-2059 (C.G.-G.); 0000-0001-7567-1798 (G.P.); 0000- 0001-6853-3063 (C.G.). but recently, Weiss et al. (18) showed an association between MAS and elevated serum levels of free IL-18. Received for publication February 19, 2020. Accepted for publication June 15, 2020. High levels of free IL-18 have been measured in patients with MAS This work was supported by Swiss National Science Foundation Grant 310030_712674, the Institute of Rheumatology Research, and the Rheumasearch secondary to sJIA (18). More importantly, a child with sJIA and Foundation. recurrent episodes of severe MAS was successfully treated by the Address correspondence and reprint requests to Prof. Cem Gabay, Division administration of recombinant human IL-18BP (tadekinig alfa) (19). of Rheumatology, Department of Medicine, University Hospitals of Geneva, Using a murine model of MAS induced by repeated CpG in- 26 Avenue de Beau-Se´jour, CH-1211 Geneva 14, Switzerland. E-mail address: [email protected] jections (20, 21), we recently showed that Il-18bp–deficient (Il- 2/2 The online version of this article contains supplemental material. 18bp ) mice developed a more severe form of the disease (22). In addition, serum levels of free Il-18 were detectable only in Il- Abbreviations used in this article: BM, bone marrow; fHLH, familial HLH; HLH, 2/2 hemophagocytic lymphohistiocytosis; IL-18BP, IL-18 binding protein; Il-18bp2/2, 18bp but not in wild-type (WT) mice following CpG stimu- 2 2 Il-18bp–deficient; KO, knockout; KO→KO, Il-18bp / BM transplanted into Il- lation and correlated with a more pronounced Ifn-g signature and 18bp2/2 recipient mice; KO→WT, Il-18bp2/2 BM transplanted into WT recipient mice; MAS, macrophage activation syndrome; pt-Il18bp, primary Il18bp transcript; clinical and biological signs of MAS. These findings support the sJIA, systemic juvenile idiopathic arthritis; WT, wild-type; WT→KO, WT BM trans- hypothesis that an imbalance between Il-18 and Il-18bp levels is 2/2 planted into Il-18bp recipient mice; WT→WT, WT BM transplanted into WT involved in the pathogenesis of MAS. recipient mice. Previous in vitro studies showed that Il-18bp is expressed by a Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 variety of cell types, but little is known regarding the regulation of www.jimmunol.org/cgi/doi/10.4049/jimmunol.2000168 2 RADIOSENSITIVE AND RADIORESISTANT CELLS PRODUCE IL-18BP Il-18bp production in vivo. Most importantly, several in vitro studies A noncommercial rabbit anti-mouse IL-18BP Ab provided by MAB Dis- showed that IL-18BP production is enhanced in response to IFN-g, covery GmbH (Neuried, Germany) served to coat 96-well plates (dilution thus acting as a negative feedback loop to dampen IL-18 activities in PBS to 1 mg/ml). Nonspecific binding was blocked with 1% BSA (Sigma-Aldrich) in PBS. The range of Il-18bp standard (recombinant (4, 7, 23–28). In this study, we show that both radioresistant and mouse Il-18bp isoform d; Creative BioMart) was from 20 to 0.156 ng/ml. radiosensitive cells produce Il-18bp during CpG-induced MAS but A goat anti-mouse Il-18bp isoform c–biotinylated Ab (Bio-Techne) was that their relative contribution varies according to the organ exam- used as the detection Ab. The samples and standards were diluted in PBS– ined. Furthermore, Il-18bp is produced as an Ifn-g signature gene in 1% BSA. In addition, to verify that this assay detects both the unbound form of Il-18bp as well as Il-18bp bound to mature Il-18, recombinant response to CpG injection but not in naive mice. mouse Il-18bp (3ng/ml in PBS, 1% BSA) was preincubated without or with recombinant mouse mature Il-18 at five different concentrations Materials and Methods ranging from 3 pg/ml to 30 ng/ml for 15 min before assessment of Il-18bp Mice and treatments concentrations. Il-18bp quantification was not affected by addition of Il-18, indicating that this ELISA recognizes both the uncomplexed form of Il- Frozen C57BL/6N Il18bptm1.1(KOMP)Vlcg (Il-18bp+/2) mouse embryos, 18bp and Il-18bp bound to mature Il-18 (data not shown). generated by the Knockout Mouse Project Repository (University of For both mature free Il-18 and Il-18bp measurements, after washing the California, Davis, Davis, CA), were purchased and implanted into the detection Ab, peroxidase-conjugated streptavidin (Jackson Immuno- uterus of foster females to obtain Il-18bp+/2 mice, which were maintained research Europe, Newmarket, U.K.) diluted in PBS–1% BSA was added. at Charles River Laboratories (L’Arbresle, France).
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