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The farnesoid-X-receptor in myeloid cells controls CNS autoimmunity in an IL-10-dependent fashion

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Abstract

Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity. Pharmacological FXR activation promoted generation of anti-inflammatory macrophages characterized by arginase-1, increased IL-10 production, and suppression of T cell responses. In mice, FXR activation ameliorated CNS autoimmunity in an IL-10-dependent fashion and even suppressed advanced clinical disease upon therapeutic administration. In analogy to rodents, pharmacological FXR activation in human monocytes from healthy controls and MS patients induced an anti-inflammatory phenotype with suppressive properties including control of effector T cell proliferation. We therefore, propose an important role of FXR in control of T cell-mediated autoimmunity by promoting anti-inflammatory macrophage responses.

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Acknowledgments

We thank Annika Engbers, Andrea Pabst and Corinna Hölscher for excellent technical support as well as Anita Posevitz-Fejfar and Verena Schütte for bio-banking of human PBMC samples. We thank Heike Blum for creating an excellent illustration (Fig. 8). We thank M.E. Schwab and H.-J. Radzun for providing antibodies against NogoA and KiM1P to perform histological analysis. This study was supported by the German Research Foundation Grant Number CRC 128 A8 to LK, CRC 128 Z1 to TK, and CRC 128 Z2 to HW,FZ, BH and the Interdisciplinary center for clinical research (IZKF) Grant Number Kl2/015/14 to LK.

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    Authors and Affiliations

    1. Department of Neurology, University of Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany

      Stephanie Hucke, Martin Herold, Maren Lindner, Ann-Katrin Fleck, Juncal Fernandez-Orth, Sven G. Meuth, Heinz Wiendl & Luisa Klotz

    2. Institute of Immunology, University of Muenster, Muenster, Germany

      Marie Liebmann, Nicole Freise, Stefanie Zenker & Johannes Roth

    3. Institute of Experimental Immunology and Imaging, University Duisburg-Essen, Essen, Germany

      Stephanie Thiebes & Daniel Robert Engel

    4. Department of Neurology, Technische Universität München, Munich, Germany

      Dorothea Buck & Bernhard Hemmer

    5. Department of Neurology, University of Mainz, Mainz, Germany

      Felix Luessi & Frauke Zipp

    6. Cluster of Excellence Cells in Motion, University of Muenster, Muenster, Germany

      Sven G. Meuth & Heinz Wiendl

    7. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

      Bernhard Hemmer

    8. Institute of Neuropathology, University of Muenster, Muenster, Germany

      Tanja Kuhlmann

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    Corresponding author

    Correspondence to Luisa Klotz.

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    Conflict of interest

    The authors declare no competing financial interests. MH, ML, NF, ML, AF, SZ, ST, JF, DRE, BH, JR have nothing to declare. SH received speaker honoraria from Novartis. DB received compensation for activities with Bayer HealthCare, BiogenIdec, MerckSerono, and Novartis, she was supported by the Abirisk and the PML Consortium. FL received travel grants from Teva Pharmaceuticals and Merck Serono. SGM received honoraria for lecturing and travel expenses for attending meetings and financial research support from Bayer, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, MSD, Novartis, Omniamed, Novo Nordisk, Sanofi-Aventis and Teva. FZ has received research grants from Teva, Merck Serono, Novartis and Bayer as well as consultation funds from Teva, Merck Serono, Novartis, Bayer Healthcare, Biogen Idec Germany, ONO, Genzyme, Sanofi-Aventis and Octapharma, her travel compensation has been provided for by the aforementioned companies. TK received speaker honoraria from Novartis, Biogen Idec Canada,and Teva; she received compensation as a consultant from Genzyme. HW received compensation for serving on Scientific Advisory Boards/Steering Committees for Bayer Healthcare, Biogen Idec, Genzyme, Merck Serono, Novartis and Sanofi-Aventis; he received speaker honoraria and travel support from Bayer Vital GmbH, Bayer Schering AG, Biogen Idec, CSL Behring, Fresenius Medical Care, Genzyme, Glaxo Smith Kline, GW Pharmaceuticals, Lundbeck, Merck Serono, Omniamed, Novartis and Sanofi-Aventis; he received compensation as a consultant from Biogen Idec, Merck Serono, Novartis and Sanofi-Aventis, has received research support from Bayer Vital, Biogen Idec, Genzyme Merck Serono, Novartis, Sanofi-Aventis Germany, Sanofi US. LK received compensation for serving on Scientific Advisory Boards for Genzyme and Novartis; she received speaker honoraria and travel support from Novartis, Merck Serono and CSL Behring; she receives research support from Novartis and Biogen Idec.

    Additional information

    S. Hucke and M. Herold contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    401_2016_1593_MOESM1_ESM.jpg

    Supplementary Figure 1. FXR expression in peripheral immune cells is reduced in CNS autoimmunity. a-d Nuclear receptor (NR) expression in human and murine immune cells was determined by quantitative real-time RT-PCR. Data were normalized to endogenous 18s expression and are displayed as relative expression compared to control group, which was set to 1. Shown are boxplots where each box displays the upper and lower quartiles of the respective distribution, median (line), and mean (+). Box whiskers represent the maximum and minimum range. a FXR mRNA expression in HD and MS patients from cohort 1 split according to treatment allocation, i.e., untreated, first-line immune-modulatory treatment, or escalation therapy. b+c Equal 18s expression by PBMCs from HD and MS patients demonstrates comparable RNA quality. Expression of NRs in b cohort 1 (n=14 healthy donors (HD), n=30 MS patients (RRMS)) and c cohort 2 (n=15 HD, n=15 MS patients (RRMS)). d Expression of the indicated NRs was analyzed in splenocytes from EAE-diseased mice (mean clinical score of 3.4±0.62, n=15) compared to splenocytes from healthy C57BL/6 mice. (n=16 per group) *p<0.05; **p<0.01; ***p<0.001. (JPEG 2551 kb)

    401_2016_1593_MOESM2_ESM.jpg

    Supplementary Figure 2. FXR activation does not generally alter cytokine production of lymph node T cells during EAE. EAE was performed as described in Fig. 2c. On day 15 of EAE, lymph node cells were ex vivo restimulated with αCD3 for 48h. Then, cytokine production in supernatants was analyzed by Luminex® Multiplex Assay. Shown are boxplots where each box displays the upper and lower quartiles of the respective distribution and median (line). Box whiskers represent the maximum and minimum range. (n=8 per group) (JPEG 1507 kb)

    401_2016_1593_MOESM3_ESM.jpg

    Supplementary Figure 3. In vivo FXR activation induces expression of FXR target genes but does not alter composition and phenotype of myeloid cell populations in gut and intestine. a+b EAE was performed as described in Fig. 2b. a On day 15, liver and intestine of EAE-diseased mice treated with GW4064 in 0.5 % CMC or vehicle only (DMSO in 0.5 % CMC) were collected and expression of FXR target genes ApoE and SHP was analyzed by quantitative real-time RT-PCR. Data were normalized to endogenous 18s expression and are displayed as mean relative expression compared to DMSO-treated EAE mice ± SEM. (n=3 per group) *p<0.05; **p<0.01. b In addition, liver (n=15) and intestine (n=3) were subjected to HE staining and histological analysis. Liver and intestine exhibit normal histology, which indicates that GW4064-treatment does not exhibit toxic side effects. c–f After 7 days of oral treatment of healthy mice with GW4064 or vehicle only (w/o EAE) or on day 10 after EAE induction (EAE) in GW4064- or control-treated mice, single cell suspensions from livers c+d or intestine e+f were analyzed for composition of different myeloid cell subpopulations by flow cytometry as described in supplementary table II (n=8). Panels c (liver) and e (intestine) depict our gating strategy for myeloid cell subpopulations using the markers CD11b, Gr1, Ly-6C, Ly-6G, and F4/80 in livers c and intestines e. c-f Additionally, we assessed expression levels of the well-known activation markers MHC class II, CD40, and CD80, as well as the anti-inflammatory markers B7H1 and MR, on different myeloid cell subsets as gated in c and e, respectively. g Intestinal cell suspensions from EAE-diseased mice were further used to determine mRNA expression levels of classical M1 and M2 markers by quantitative real-time RT-PCR (n=8). Data were normalized to endogenous HPRT expression ± SEM. (JPEG 4429 kb)

    401_2016_1593_MOESM4_ESM.jpg

    Supplementary Figure 4. GW4064 does not affect survival and proliferation of immune cells. a+b Human CD4+ T cells were isolated from the peripheral blood of healthy donors (n=3). T cells were treated with 15 μM GW4064 and stimulated in the presence of αCD3 and αCD28. a Survival and b proliferation were analyzed by flow cytometric analysis after 48h and 72h. a Graph depicts the mean percentage of live cells ± SEM after 48h and 72h, which were identified as Hoechst33342- demonstrating no toxic effect on T cells. b Graph depicts the mean percentage of proliferating T cells ± SEM, which is unaltered under GW4064-treatment. c Human CD14+ monocytes were isolated from the peripheral blood of healthy donors (n=3) and were treated with 15 μM GW4064. Graph depicts the mean percentage of live cells ± SEM after 48h and 72h, which were identified as Hoechst33342- demonstrating no toxic effect on monocytes. d+e Analysis of survival and proliferation of murine splenic CD4+ T cells treated with 15 μM GW4064 and stimulated in the presence of αCD3 and αCD28 was performed as in a+b. f BMMs were differentiated in the presence of 15 μM GW4064. On day 7 of differentiation, BMMs were harvested and survival was determined by flow cytometric analysis of Hoechst33342 staining after 48h and 72h of cultivation. Graph depicts the mean percentage of live cells ± SEM demonstrating no toxic effect on macrophages. (JPEG 1228 kb)

    401_2016_1593_MOESM5_ESM.jpg

    Supplementary Figure 5. GW4064 does not affect cytokine production by macrophages. BMMs were differentiated in the presence of 15 μM GW4064. On day 7 of differentiation, BMMs were harvested and seeded to determine cytokine production, which was analyzed by Luminex® Multiplex Assay after 48h of cultivation in the presence or absence of GW4064. Graphs display the pooled result from 4 independent experiments. Shown are boxplots where each box displays the upper and lower quartiles of the respective distribution and median (line). Box whiskers represent the maximum and minimum range. (JPEG 1016 kb)

    401_2016_1593_MOESM6_ESM.jpg

    Supplementary Figure 6. FXR activation in human myeloid cells represents a new therapeutic target. a CD14+ monocytes were isolated from the peripheral blood of healthy donors (HD) and treated with 15 μM GW4064. After 24h, monocytes were washed twice and subsequently cocultured with CD3+ T cells isolated from the blood of syngen or allogen healthy donors patients in the presence of 1 μg/ml anti-CD3 and 1 μg/ml anti-CD28. After 72h, proliferation was assessed by flow cytometric analysis of proliferation dye eFluor670 (see histograms Fig.7b). Graphs display the mean percentage of proliferated CD8+ T cells as well as the mean division index ± SEM. b CD14+ monocytes were isolated from the peripheral blood of healthy donors (HD) or MS patients (MS) and treated with 15 μM GW4064. After 24h, monocytes were washed twice and subsequently cocultured with CD3+ T cells isolated from the blood of allogen MS patients in the presence of 1 μg/ml anti-CD3 and 1 μg/ml anti-CD28. After 72h, proliferation was assessed by flow cytometric analysis of proliferation dye eFluor670 (see histograms Fig. 7c). Graphs display the mean percentage of proliferated CD8+ T cells as well as the mean division index ± SEM. c Upper row: Summary of all assays run in Fig. 7b+c. Lower row: In addition, the relative proliferation of CD8+ T cells was calculated by dividing the percentage of dividing cells (GW4064-treated monocyte group) / (control monocyte group). *p<0.05; **p<0.01; ***p<0.001. (JPEG 1504 kb)

    Supplementary Table I. Description of patient data 8 (DOCX 16 kb)

    Supplementary Table II. Immune cell isolation (DOCX 16 kb)

    Supplementary Table III. Antibodies used in this study (DOCX 15 kb)

    401_2016_1593_MOESM10_ESM.docx

    Supplementary Table IV. Primers, QuantiTect Primer Assays (Qiagen) or TaqMan probes used for real-time RT-PCR analysis (DOCX 19 kb)

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    Hucke, S., Herold, M., Liebmann, M. et al. The farnesoid-X-receptor in myeloid cells controls CNS autoimmunity in an IL-10-dependent fashion. Acta Neuropathol 132, 413–431 (2016). https://doi.org/10.1007/s00401-016-1593-6

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