The TLR9 Agonist Cobitolimod Induces IL10-Producing Wound Healing Macrophages and Regulatory T Cells in Ulcerative Colitis

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Abstract

Background and Aims

The topically applied Toll-like receptor 9 [TLR9] agonist cobitolimod is a first-in-class DNA-based oligonucleotide with demonstrated therapeutic efficacy in clinical trials with ulcerative colitis [UC] patients. We here characterized its anti-inflammatory mechanism in UC.

Methods

Luminal cobitolimod administration was evaluated in an experimental dextran sodium sulfate [DSS]-induced colitis model. Cultured blood and mucosal cells from UC patients were treated with cobitolimod and analysed via microarray, quantitative real-time PCR, ELISA and flow cytometry. Intestinal slides of cobitolimod-treated UC patients were analysed by immunohistochemistry.

Results

Cobitolimod administration markedly suppressed experimental colitis activity, and microarray analyses demonstrated mucosal IL10 upregulation and suppression of IL17 signalling pathways. Cobitolimod treatment was associated with significant induction of mucosal IL10+Tr1 and Treg cells and suppression of Th17 cells. TLR9 knockout mice indicated that cobitolimod requires TLR9 signalling for IL10 induction. In UC patients, mucosal TLR9 levels correlated with severity of inflammation. Cobitolimod inhibited IL17A and IL17F, but increased IL10 and FoxP3 expression in cultured intestinal UC T cells. Cobitolimod-mediated suppression of intestinal IL17+T cells was abrogated by IL10 blockade. Furthermore, cobitolimod led to heightened IL10 production by wound healing macrophages. Immunohistochemistry in intestinal biopsies of cobitolimod-treated UC patients indicated increased presence of IL10+mononuclear and regulatory T cells, as well as reduction of IL17+cells.

Conclusion

Activation of TLR9 via cobitolimod might represent a novel therapeutic approach in UC, as it suppresses Th17 cells and induces anti-inflammatory IL10+macrophages and regulatory T cells, thereby modifying the dysregulated intestinal cytokine balance.

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Most cited references 43

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Infliximab for induction and maintenance therapy for ulcerative colitis.

Paul Rutgeerts, William J Sandborn, Brian Feagan … (2005)

Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor alpha, is an established treatment for Crohn's disease but not ulcerative colitis. Two randomized, double-blind, placebo-controlled studies--the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively)--evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2. In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P<0.001 for both comparisons with placebo). A response was defined as a decrease in the Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute rectal-bleeding subscore of 0 or 1. In ACT 2, 64 percent of patients who received 5 mg of infliximab and 69 percent of those who received 10 mg had a clinical response at week 8, as compared with 29 percent of those who received placebo (P<0.001 for both comparisons with placebo). In both studies, patients who received infliximab were more likely to have a clinical response at week 30 (P< or =0.002 for all comparisons). In ACT 1, more patients who received 5 mg or 10 mg of infliximab had a clinical response at week 54 (45 percent and 44 percent, respectively) than did those who received placebo (20 percent, P<0.001 for both comparisons). Patients with moderate-to-severe active ulcerative colitis treated with infliximab at weeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo. (ClinicalTrials.gov numbers, NCT00036439 and NCT00096655.) Copyright 2005 Massachusetts Medical Society.

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CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages.

Machteld Tiemessen, Ann Jagger, Hayley G Evans … (2007)

CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are potent suppressors of the adaptive immune system, but their effects on innate immune cells are less well known. Here we demonstrate a previously uncharacterized function of Tregs, namely their ability to steer monocyte differentiation toward alternatively activated macrophages (AAM). AAM are cells with strong antiinflammatory potential involved in immune regulation, tissue remodeling, parasite killing, and tumor promotion. We show that, after coculture with Tregs, monocytes/macrophages display typical features of AAM, including up-regulated expression of CD206 (macrophage mannose receptor) and CD163 (hemoglobin scavenger receptor), an increased production of CCL18, and an enhanced phagocytic capacity. In addition, the monocytes/macrophages have reduced expression of HLA-DR and a strongly reduced capacity to respond to LPS in terms of proinflammatory mediator production (IL-1beta, IL-6, IL-8, MIP-1alpha, TNF-alpha), NFkappaB activation, and tyrosine phosphorylation. Mechanistic studies reveal that CD4(+)CD25(+)CD127(low)Foxp3(+) Tregs produce IL-10, IL-4, and IL-13 and that these cytokines are the critical factors involved in the suppression of the proinflammatory cytokine response. In contrast, the Treg-mediated induction of CD206 is entirely cytokine-independent, whereas the up-regulation of CD163, CCL18, and phagocytosis are (partly) dependent on IL-10 but not on IL-4/IL-13. Together these data demonstrate a previously unrecognized function of CD4(+)CD25(+)Foxp3(+) Tregs, namely their ability to induce alternative activation of monocytes/macrophages. Moreover, the data suggest that the Treg-mediated induction of AAM partly involves a novel, cytokine-independent pathway.

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Author and article information

Journal

Journal ID (nlm-ta): J Crohns Colitis

Journal ID (iso-abbrev): J Crohns Colitis

Journal ID (publisher-id): eccojc

Title: Journal of Crohn's & Colitis

Publisher: Oxford University Press (UK )

ISSN (Print): 1873-9946

ISSN (Electronic): 1876-4479

Publication date (Print): May 2020

Publication date (Electronic): 20 October 2019

Publication date PMC-release: 20 October 2019

Volume: 14

Issue: 4

Pages: 508-524

Affiliations

[1 ] First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg , Erlangen, Germany

[2 ] Institute of Pathology, Klinikum Bayreuth , Bayreuth, Germany

[3 ] Internal Medicine Department, University Tor Vergata , Rome, Italy

[4 ] Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg , Erlangen, Germany

[5 ] Department of Surgery, Friedrich-Alexander-University Erlangen-Nürnberg , Erlangen, Germany

[6 ] Department for Anesthesiology, Friedrich-Alexander-University Erlangen-Nürnberg , Erlangen, Germany

[7 ] Department of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg , Erlangen, Germany

[8 ] InDex Pharmaceuticals , Stockholm, Sweden

Author notes

Corresponding author: Prof. Raja Atreya, MD, First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany. Tel: 49 9131 85 35115; Fax: 49 9131 85 35116; Email: raja.atreya@ 123456uk-erlangen.de .

Markus F. Neurath and Raja Atreyaa contributed equally.

Article

Publisher ID: jjz170

DOI: 10.1093/ecco-jcc/jjz170

PMC ID: 7242005

PubMed ID: 31630153

SO-VID: f6ad9d10-d3fc-43ce-9e47-384b0104b942

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Page count

Pages: 17

Funding

Funded by: InDex Pharmaceuticals AB;

Award ID: CRC1181

Award ID: DFG-SFB/TRR241

Funded by: German Research Council;

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The TLR9 Agonist Cobitolimod Induces IL10-Producing Wound Healing Macrophages and Regulatory T Cells in Ulcerative Colitis

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Most cited references 43

Infliximab for induction and maintenance therapy for ulcerative colitis.

Ulcerative colitis.

CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages.

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