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Induction by Lupus Immune Complexes Differentially Regulate Plasmacytoid Dendritic Cells and C1q Differentially Regulate Inflammatory Gene Induction by Lupus Immune Complexes This information is current as Deanna M. Santer, Alice E. Wiedeman, Thomas H. Teal, of September 23, 2021. Pradipta Ghosh and Keith B. Elkon J Immunol published online 5 December 2011 http://www.jimmunol.org/content/early/2011/12/04/jimmun ol.1102797 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2011/12/05/jimmunol.110279 Material 7.DC1 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 © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published December 5, 2011, doi:10.4049/jimmunol.1102797 The Journal of Immunology Plasmacytoid Dendritic Cells and C1q Differentially Regulate Inflammatory Gene Induction by Lupus Immune Complexes Deanna M. Santer,* Alice E. Wiedeman,* Thomas H. Teal,† Pradipta Ghosh,† and Keith B. Elkon*,† Immune complexes (ICs) play a pivotal role in causing inflammation in systemic lupus erythematosus (SLE). Yet, it remains unclear what the dominant blood cell type(s) and inflammation-related gene programs stimulated by lupus ICs are. To address these ques- tions, we exposed normal human PBMCs or CD14+ isolated monocytes to SLE ICs in the presence or absence of C1q and performed microarray analysis and other tests for cell activation. By microarray analysis, we identified genes and pathways regulated by SLE ICs that are both type I IFN dependent and independent. We also found that C1q-containing ICs markedly reduced expression of the majority of IFN-response genes and also influenced the expression of multiple other genes induced by SLE ICs. Surprisingly, IC activation of isolated CD14+ monocytes did not upregulate CD40 and CD86 and only modestly Downloaded from stimulated inflammatory gene expression. However, when monocyte subsets were purified and analyzed separately, the low- abundance CD14dim (“patrolling”) subpopulation was more responsive to ICs. These observations demonstrate the importance of plasmacytoid dendritic cells, CD14dim monocytes, and C1q as key regulators of inflammatory properties of ICs and identify many pathways through which they act. The Journal of Immunology, 2012, 188: 000–000. ystemic lupus erythematosus (SLE) is a multisystem au- plement components downstream of C3, especially release of C3a http://www.jimmunol.org/ toimmune disease characterized by the presence of high and C5a that promote chemotaxis and inflammation as well as S titer autoantibodies directed against self nucleoproteins deposition of C5b-9 together, that promote tissue injury (11–13). (reviewed in Ref. 1). Some of these Abs interact with Ags to form More recently, C1q has been shown to protect against SLE by immune complexes (ICs) that deposit in the kidneys, skin, and vas- a separate effect, via preventing the stimulation of type I IFN (14, culature (2, 3). ICs also directly engage FcgRs expressed on mac- 15). We observed that, in the absence of C1q, ICs bind to FcgRII rophages and neutrophils, resulting in the release of proinflammatory on plasmacytoid dendritic cells (pDCs) and potently stimulate cytokines, proteolytic enzymes, and reactive oxygen intermediates IFN-a production, whereas C1q-containing ICs (C1q-ICs) bound (4). Thus, ICs, especially after complement activation, are thought to predominantly to monocytes, and IFN-a production by pDCs was be the predominant inducers of tissue injury in SLE (3, 5). markedly attenuated (15). Although C1q-ICs did not stimulate by guest on September 23, 2021 Despite these findings, individuals with loss-of-function muta- monocytes to produce soluble factors such as IL-10 or TNF-a that tions of the first complement component, C1q, almost invariably could explain IFN-a suppression, we could not exclude the pos- develop SLE (reviewed in Ref. 6). This “lupus paradox” (7), in sibility that ICs induce a ligand on monocytes that engages one of which complement activation promotes tissue injury, yet comple- the many inhibitory receptors on pDCs. ment deficiency predisposes to SLE, has, in part, been reconciled To obtain comprehensive data of genes differentially regulated by studies demonstrating the protective role of classical comple- by exposure of blood cells to SLE ICs, to determine how this profile ment pathway components (C1-4) in facilitating the clearance of is altered in the presence of C1q-ICs, and to evaluate the in- lupus Ags (apoptotic debris) (8–10). In contrast, it is the com- flammatory properties of ICs on monocytes in the absence of pDCs, we performed gene expression analysis of peripheral blood as well as isolated monocytes stimulated by ICs or C1q-ICs. Our results *Department of Immunology, School of Medicine, University of Washington, Seattle, WA 98195; and †Division of Rheumatology, School of Medicine, University of enable comparison between the in vitro effects of ICs and ex vivo Washington, Seattle, WA 98195 inflammatory gene transcript profiles as well as those genes reg- Received for publication September 27, 2011. Accepted for publication November 3, ulated by C1q. They also show limited CD14+ monocyte stimu- 2011. lation by ICs in the absence of pDCs and suggest relevant genes This work was supported by National Institutes of Health Grants AR48796 and and pathways that should prove productive for future investigation NS065933. D.M.S. was supported by a Natural Sciences and Engineering Research Council of Canada postgraduate scholarship and a Kirkland scholarship. of SLE pathogenesis. The microarray data presented in this article have been submitted to the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc= GSE32285) under Series accession number GSE32285. Materials and Methods Reagents Address correspondence and reprint requests to Dr. Keith B. Elkon, Division of Rheumatology, University of Washington, 1959 NE Pacific Street, Box 356428, Purified C1q protein was purchased from Complement Technology. Neu- Seattle, WA 98195. E-mail address: [email protected] tralizing Ab to IFN-a was purchased from Millipore. Loxoribine was The online version of this article contains supplemental material. purchased from Invivogen. All reagents had ,0.06 EU/ml endotoxin by Abbreviations used in this article: C1q-IC, C1q-containing immune complex; GOI, Limulus amebocyte lysate clot assay (Cape Cod Associates). gene of interest; IC, immune complex; IP-10, IFN-g–inducible protein-10; ISG, IFN- stimulated gene; MFI, mean fluorescent intensity; pDC, plasmacytoid dendritic cell; Patients qRT-PCR, quantitative real-time PCR; SLC16A10, solute carrier family 16, member 10; SLE, systemic lupus erythematosus. All SLE patients fulfilled the American College of Rheumatology 1982 revised criteria for the classification of SLE (16). All serum samples were Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 collected with the respective institutions’ review board approval. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102797 2 IMMUNE COMPLEX GENE ARRAYS Cell purification genuity software. In some cases, changes in gene expression of 2-fold or greater were analyzed separately. Functional analysis of differentially PBMCs were prepared from healthy human donors or SLE patients using expressed genes was performed using Ingenuity pathways analysis (Inge- Ficoll-Paque density gradient centrifugation. For normal donor experi- nuity Systems). Some genes considered were not eligible for Ingenuity ments, a different healthy donor was used for each independent experiment. pathway analysis, but are included in the Venn diagrams. The significance In certain experiments, pDCs were depleted from PBMCs using BDCA-4 of the association between the data set and the canonical pathway was , magnetic beads (Miltenyi Biotec) with 0.03% remaining in each ex- measured using Fisher’s exact test to calculate a p value representing the periment. As an additional control, PBMCs were mock depleted by in- probability that the association between the transcripts in the data set and cubating cells without beads, but still placed through the magnetic column. the canonical pathway was explained by chance alone. Canonical functions Total monocytes were purified from PBMCs by positive selection with were also determined, and networks were overlaid with expression data . CD14 magnetic beads (Miltenyi Biotec) with consistent purities of 95% from the data set. IFN-stimulated genes (ISGs) were identified by exam- and undetectable percentages of contaminating pDCs. In certain experi- ining eight publications (22–29) plus the interferome.org database specifi- . ments, monocyte subsets were sorted to purities of 90–95% using cally for type I IFN (30). methods described by others (17). Briefly, cells were stained with the following fluorescently
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