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Igg Immunocomplexes Sensitize Human Monocytes for Inflammatory IgG Immunocomplexes Sensitize Human Monocytes for Inflammatory Hyperactivity via Transcriptomic and Epigenetic Reprogramming in Rheumatoid Arthritis This information is current as of September 28, 2021. Qiao Zhong, Fang-Yuan Gong, Zheng Gong, Sheng-Hao Hua, Ke-Qin Zeng and Xiao-Ming Gao J Immunol published online 30 April 2018 http://www.jimmunol.org/content/early/2018/04/27/jimmun ol.1701756 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2018/04/28/jimmunol.170175 Material 6.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 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 © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published April 30, 2018, doi:10.4049/jimmunol.1701756 The Journal of Immunology IgG Immunocomplexes Sensitize Human Monocytes for Inflammatory Hyperactivity via Transcriptomic and Epigenetic Reprogramming in Rheumatoid Arthritis Qiao Zhong,*,†,‡ Fang-Yuan Gong,* Zheng Gong,* Sheng-Hao Hua,* Ke-Qin Zeng,*,x and Xiao-Ming Gao*,{,‖ Prevalence of circulating immunocomplexes (ICs) strongly correlates with rheumatoid arthritis (RA) in humans. Deposits of IgG-ICs are abundant in affected joints of patients, yet molecular mechanisms for the pathogenic roles of such ICs are not fully understood. In this study, we present evidence that IgG-ICs precipitated from RA sera sensitized human monocytes for a long- lasting inflammatory functional state, characterized by a strong TNF-a response to cellular proteins representing damage- associated molecular patterns and microbe-derived pathogen-associated molecular patterns. Importantly, plate-coated human Downloaded from IgG (a mimic of deposited IC without Ag restriction) exhibited a similarly robust ability of monocyte sensitization in vitro. The plate-coated human IgG–induced functional programming is accompanied by transcriptomic and epigenetic modification of various inflammatory cytokines and negative regulator genes. Moreover, macrophages freshly isolated from synovia of patients with RA, but not sera-negative arthropathy, displayed a signature gene expression profile highly similar to that of IC-sensitized human monocytes, indicative of historical priming events by IgG-ICs in vivo. Thus, the ability of IgG-ICs to drive sustainable functional sensitization/reprogramming of monocytes and macrophages toward inflammation may render them key players in the http://www.jimmunol.org/ development of RA. The Journal of Immunology, 2018, 200: 000–000. roduction of autoantibodies is the hallmark of systemic Inflammatory cytokines, predominantly TNF-a, IL-1b, IL-6, autoimmune disorders such as rheumatoid arthritis (RA), a and IL-8, are crucial players in the pathogenesis of RA (11). P chronic inflammatory disease of the joints occurring in Tissue macrophages and infiltrating monocytes are considered the ∼1% of the population worldwide. There is ample evidence sug- main source of inflammatory cytokines in affected joints of RA gesting that such autoantibodies are not merely side products of patients. Human CD14+ monocytes represent ∼5% of the WBCs. overactivation of the adaptive immune system but are important After transient circulation in the bloodstream, these highly plastic contributing factors in the pathogenesis process of the disease cells enter peripheral tissues (e.g., joint synovium) and can dif- by guest on September 28, 2021 (1, 2), particularly in the form of IgG immunocomplexes (ICs) ferentiate into dendritic cells, macrophages, or osteoclasts in a capable of interacting with myeloid cells through receptors for the contact-dependent manner. Both types of inflammatory cytokine– Fc fragment of Ig H chains (FcgRs) (3, 4). It has been shown that producing M1 and anti-inflammatory M2 macrophages are known the incidence and severity of erosive bone damage in RA posi- to be present in inflamed synovia of RA patients (12). Interest- tively correlate with the titers of anticitrullinated peptide Ab and ingly, recent advances indicate that costimulation through FcgRs rheumatoid factor (anti-IgG autoantibody) (5) and also that de- and TLRs could not only elicit inflammatory cytokine production posits of IgG-ICs are abundant in affected joints of RA patients by M2 macrophages but also drive M2–M1 macrophage conver- and in animal models of RA, in which autoantibodies are sion (13). More importantly, functional analysis and gene ex- demonstrably pathogenic (1, 2, 6). It is also evident that ICs pression profiling on freshly isolated synovial macrophages from containing RA-related IgG autoantibodies against vimentin, fi- RA patients revealed an altered biologic response to IL-10, with brinogen, or lactoferrin (LTF) are potent activators of myeloid attenuation of its anti-inflammatory function and a concomitant cells via simultaneous ligation of FcgRs and TLRs (2, 7–10). retention of IFN-g–like activating functions (14). Despite these *Institute of Biology and Medical Sciences, School of Biology and Basic Medical The online version of this article contains supplemental material. Sciences, Soochow University, Suzhou 215123, China; †Department of Laboratory Abbreviations used in this article: ChIP, chromatin immunoprecipitation; cIgG, plate- Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou x coated human IgG; CRT, calreticulin; DAMP, damage-associated molecular pattern; 215002, China; ‡Suzhou Municipal Hospital, Suzhou 215002, China; Department of DEG, differentially expressed gene; FDR, false discovery rate; GO, gene ontology; Rheumatology, The First Affiliated Hospital of Soochow University, Suzhou 215001, { GSEA, gene set enrichment analysis; HC-IC, IC precipitated from serum of healthy China; Jiangsu Key Laboratory of Infection and Immunity, Suzhou 215123, China; ‖ control; HMT, histone methyltransferase; IC, immunocomplex; LTF, lactoferrin; and Key Laboratory of Systemic Biomedical Study, Suzhou 215123, China LTF-IC, LTF-containing IC; Mo(cIgG), human monocyte primed with cIgG for ORCID: 0000-0002-6381-5632 (K.-Q.Z.). 24 h; Mo(cIgG/LPS), human monocyte primed with cIgG for 24 h followed by a 2 h LPS (10 ng/ml) stimulation; Mo(RPMI), human monocyte cultured in R10 Received for publication December 19, 2017. Accepted for publication April 4, 2018. medium alone for 24 h; Mo(RPMI/LPS), human monocyte cultured in R10 medium This work was supported by grants from the Ministry of Science and Technology alone for 24 h followed by a 2 h LPS (10 ng/ml) stimulation; NES, normalized (2017YFA0104502), the Ministry of Education (IRT1075), and the Natural Science enrichment score; PAMP, pathogen-associated molecular pattern; RA, rheumatoid ar- Foundation of China (31570868/31770942). thritis; RA-IC, IC precipitated from serum of RA patient; SF, synovial fluid; SpA, spondyloarthropathy; TSS, transcriptional start site. The sequences presented in this article have been submitted to the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE102728. Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 Address correspondence and reprint requests to Dr. Xiao-Ming Gao, School of Bi- ology and Basic Medical Sciences, Soochow University, 199 Ren-Ai Road, Suzhou 215123, China. E-mail address: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.1701756 2 FUNCTIONAL REPROGRAMMING OF HUMAN MONOCYTES BY IgG-ICs important progresses of the recent decade, however, molecular Reagents and Abs mechanisms for the arthritogenic roles of RA-related ICs via LPS (Escherichia coli 0111:B4), zymosan (Z4250), human LTF, human monocyte/macrophage activation are still not fully understood. It IgM (no. I8260), IgA (no. I4036), and polymyxin B-agarose (no. P1411) has recently been shown that human monocytes and macrophages were from Sigma-Aldrich. Pam3CSK4 (no. tlrl-pms) and R406 were from can be trained, by exposure to Candida albicans or b-glucans, to InvivoGen. Human IVIG was from Sinopharm. Mouse IgG1 (ET901), exhibit a long-lasting enhanced functional state with a stronger IgG2b (MPC-11), mAbs against human FcgRI (CD64, 10.1) or FcgRIII (CD16, 3G8), and APC-labeled mAbs against human CD210 (3F9) were ability in proinflammatory cytokine production, phagocytosis, and from BioLegend. Mouse IgG2a (no. 16-4724-82) and mIgG3 (no. 14-4742-81) anti-infection defense, a phenomenon termed “trained immunity” were from eBioscience. Anti-human FcgRIIa mAb (CD32a, IV.3) was (15, 16). However, the question of whether deposited IgG-ICs from STEMCELL Technologies. Recombinant human IL-10 (no. 200-10) could prime monocytes/macrophages for sustainable trained was from PeproTech. Endotoxin-free recombinant human HMGB1 (no. HM-120) was from HMGBiotech. Fibrinogen prepared from human (heightened) inflammatory immunity has not been addressed. plasma (no. 341576-100MG)
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