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TNF-Anti-TNF Immune Complexes Inhibit IL-12/IL-23 Secretion by Inflammatory Macrophages Via an Fc-Dependent Mechanism

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TNF-Anti-TNF Immune Complexes Inhibit IL-12/IL-23 Secretion by Inflammatory Macrophages Via an Fc-Dependent Mechanism UvA-DARE (Digital Academic Repository) Macrophages as a therapeutic target in inflammatory bowel disease Lessons learned from anti-TNF therapy Houttuijn Bloemendaal, F.M. Publication date 2020 Document Version Other version License Other Link to publication Citation for published version (APA): Houttuijn Bloemendaal, F. M. (2020). Macrophages as a therapeutic target in inflammatory bowel disease: Lessons learned from anti-TNF therapy. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:30 Sep 2021 CHAPTER 3 TNF-anti-TNF immune complexes inhibit IL-12/IL-23 secretion by inflammatory macrophages via an Fc-dependent mechanism Felicia M. Bloemendaal, Pim J. Koelink, Karin A. van Schie, Theo Rispens, Charlotte P. Peters, Christianne J. Buskens, Jarmila D. van der Bilt, Willem. A. Bemelman, Hannelie Korf, João G. Sabino, Cyriel Y. Ponsioen, Anje A. te Velde, Geert R.A.M. D’Haens, Severine Vermeire, Gijs R. van den Brink, Manon E. Wildenberg Journal of Crohn’s and Colitis, 2018 Aug 29;12(9):1122-1130 Chapter 3 ABSTRACT Background and Aims We have recently shown that the mode of action of IgG1 anti-TNF antibodies in inflammatory bowel disease (IBD) requires Fcγ-receptor (FcγR) engagement on macrophages. Here we examine the effect of Fcγ-receptor signaling by anti-TNF on macrophage IL-12/IL-23 secretion. Methods Cytokine production by human inflammatory macrophages was assessed at the level of RNA and or protein. TNF-anti-TNF immune complex formation was determined by size-exclusion chromatography and signaling visualized by immunofluorescence. IL-12/IL- 23p40 was measured in CD14+ lamina propria cells from IBD patients. Results Infliximab and adalimumab potently suppressed IL-12/IL-23 production by inflammatory macrophages, but Fab’ fragment certolizumab did not. IL-12/IL-23 suppression depended on Syk activity and was mediated at the level of IL-12/IL-23p40 mRNA. Etanercept, a soluble TNF receptor fused to an Fc-region, did not inhibit IL-12/L-23 secretion, suggesting that the presence of an Fc-region was not sufficient. Infliximab and adalimumab formed immune complexes with soluble TNF while etanercept did not, suggesting that FcγR mediated suppression of IL-12/IL-23 required the formation of immune complexes. Indeed, non-specific IgG1 immune complexes but not uncomplexed IgG1 similarly suppressed IL-12/IL-23 secretion. Finally, infliximab significantly decreased IL-12/IL-23p40 production in myeloid cells isolated from the lamina propria of IBD patients. Conclusions TNF-anti-TNF antibody immune complexes potently inhibit IL-12/IL-23 expression by inflammatory macrophages. Our data suggest that anti-TNFs and antibodies against IL-12/IL-23 may therefore have partially overlapping modes of action in patients with IBD. 56 Anti-TNF immune complexes inhibit IL-12/IL-23 secretion INTRODUCTION In contrast to rheumatoid arthritis, the mode of action of anti-TNFs in inflammatory bowel disease (IBD) is not exclusively related to therapeutic blockade of TNF.1 We have previously demonstrated that the therapeutic efficacy of anti-TNF was completely dependent on Fc- Fcγ-receptor (FcγR) interaction in a preclinical model of colitis. Additionally, we have shown that IgG1 anti-TNFs polarize macrophages to a regulatory and wound healing phenotype in an Fc dependent manner in humans and mice.2-5 Intriguingly, it has previously been shown that activation of FcγR by immune complexes can potently inhibit IL-12 secretion by macrophages.6-8 IL-12 is a dimeric cytokine which shares its p40 subunit with IL-23. Whether immune complexes also inhibit IL-23 is not known as the 3 IL-23 specific p19 subunit had not yet been identified at the time these experiments were performed. IL-12 and IL-23 are mainly produced by macrophages and dendritic cells and play a key role in the pathogenesis of IBD. In the inflamed intestine of patients with Crohn’s disease, monocytes polarize towards an inflammatory macrophage phenotype and produce pro-inflammatory cytokines including TNF and IL-23.9 The blockade of IL-12p40 with ustekinumab, which neutralizes both IL-12 and IL-23, is currently approved as a treatment for patients with Crohn’s disease and more recently, the selective IL-23p19 inhibitors risankizumab and brazikumab showed promising results in clinical trials in patients with Crohn’s disease.10-13 Studies in ulcerative colitis are ongoing. The advent of this novel class of antibodies poses the question if patients with Crohn’s disease responding to anti-TNFs and IL-12/IL-23 blockade represent distinct or overlapping groups. TNF, IL-12 and IL-23 promote inflammation via distinct pathways, suggesting that therapies blocking these cytokines may establish mucosal healing via different routes and therefore work in different patient subgroups. However, given the fact that we have previously found that FcγR signaling is involved in the therapeutic effect of anti-TNFs and the ability of FcγR signaling to suppress IL-12 secretion, we aimed to examine how different anti-TNF blocking strategies affected macrophage IL-12/IL-23 secretion. MATERIALS AND METHODS Anti-TNF compounds Therapeutic anti-TNF compounds used in this study are adalimumab (Humira, AbbVie), infliximab (Remicade, MSD), golimumab (Simponi, MSD), certolizumab pegol (Cimzia, UCB Pharma), and etanercept (Enbrel, Pfizer). Infliximab Fab fragments were generated using the Pierce Fab micro Preparation Kit (Thermo Fisher, Landsmeer, The Netherlands). 57 Chapter 3 In vitro macrophage differentiation Peripheral blood mononuclear cells (PBMC) from healthy volunteers were isolated by Ficoll Paque density-gradient centrifugation. After washing, monocytes were isolated by Percoll density-gradient centrifugation.14 Inflammatory (M1) macrophages were obtained by culturing monocytes with IFNγ (50 ng/mL, PeproTech, London, UK) for 6 days in RPMI supplemented with 10% heat-inactivated FCS. Macrophages were then washed, reseeded and stimulated for 48 hours with LPS 100 ng/ml (Sigma, Aldrich, Zwijndrecht) and anti-TNF or IgG1 (Genetex, Irvine, CA). Complexed IgG1 was obtained by heating IgG1 at 63°C for 1 hour. Culture supernatants were harvested and cytokine levels were measured by ELISA for IL-23, IL-12p40 and IL-10 (Duoset, R&D) or by Cytometric Bead Array (Human Inflammatory Cytokine Kit, BD Biosciences). For pSYK staining, M1 macrophages were incubated with LPS and anti- TNF for 30 minutes, fixed using Fixation/Permeabilization Solution Kit (BD Biosciences) and stained for anti-pSYK-PE or isotype control staining (both Cell Signaling). Syk was inhibited with 1 μM R406 (Invivogen) added 1 hour prior to the addition of LPS and anti-TNF, cytokine production in this case was measured after 24 hours. Heat-killed bacteria Heat-killed E. coli 0111:B4 was purchased from invivogen (catalog no. tlrl-hkeb2). E. faecalis (catalog no. 29212; ATCC) was cultured in brain-heart infusion (BHI) medium. Bacteria were harvested and washed twice with PBS. Then, bacterial suspension was heated at 80°C for 30 minutes, washed, resuspended in PBS, and stored at –80°C. Complete killing was confirmed by a 72-hour incubation at 37°C. Preparation of LPMCs Intestinal mucosa was obtained from surgically resected specimens from patients with IBD, diagnosed on the basis of endoscopic and histological findings according to established criteria. All experiments were performed with mucosa from macroscopically inflamed specimens. All experiments were approved by the Medical Ethical Committee of the Academic Medical Center, Amsterdam. Written informed consent was obtained from all patients. Lamina propria mononuclear cells (LPMC) were isolated from intestinal specimens as follows; Briefly, dissected mucosa was incubated in calcium and magnesium-free HBSS containing 5 mM EDTA (Sigma-Aldrich) for 20 minutes at 37°C to remove epithelial cells. Tissues were then cut very fine and incubated in RPMI medium containing 10% FCS, 1 mg/ ml collagenase D (Roche) 1 mg/ml soybean Trypsin inhibitor (Sigma) and 50 µg/ml Dnase I (Roche) for 60 minutes at 37°C. The fraction was pelleted and resuspended in a 30% Percoll solution, then layered on 60% Percoll before centrifugation at 500 g for 10 minutes at room temperature. Viable LPMC were recovered from the 30%–60% layer interface. LPMC were then stimulated over night with heat-killed E. coli and E. faecalis both 1 × 108 cells/ 58 Anti-TNF immune complexes inhibit IL-12/IL-23 secretion ml in the presence of IgG1 or anti-TNF 10 µg/ml. Golgistop (BD Biosciences) was added after 1 hour. The next day, LPMC were stained for LIVE/DEAD® Fixable Green Dead Cell Stain Kit (Invitrogen), CD45-AF700 (Sony), CD14-PE-Cy7 (eBioscience), HLA-DR-PE, CD11b- BV421 (both Biolegend)) and then fixed using Fixation/Permeabilization Solution Kit (BD Biosciences). After fixation, cells were stained for IL-12p40-APC (Biolegend) and analyzed by FACS Fortessa (BD Biosciences) then analyzed using FlowJo software (Treestar Inc). High-performance size-exclusion chromatography (HP-SEC) Recombinant human TNF was obtained from Active Bioscience. Therapeutic anti-TNF compounds (60 µg/ml, diluted in PBS) were incubated for at least one hour with 2 µg/ml recombinant human TNF.
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