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The TLR9 agonist cobitolimod induces IL10 producing wound healing macrophages and regulatory T cells in ulcerative colitis.

Abstract

BACKGROUND AND AIMS

The topically applied Toll-like receptor 9 (TLR9) agonist cobitolimod is a first-in-class DNA-based oligonucleotide that 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 DSS-induced colitis model. Cultured blood and mucosal cells from UC patients were treated with cobitolimod and analyzed via microarray, qRT-PCR, ELISA and flow cytometry. Intestinal slides of cobitolimod treated UC patients were analyzed by immunohistochemistry.

RESULTS

Cobitolimod administration markedly suppressed experimental colitis activity and microarrays analyses demonstrated mucosal IL10 upregulation and suppression of IL17 signaling 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 signaling 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

Our studies suggest that 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.

Authors+Show Affiliations

First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany.First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany. Internal Medicine Department, University Tor Vergata, Rome, Italy.Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.Department of Surgery, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.Department for Anesthesiology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.Department of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.InDex Pharmaceuticals, Tomtebodavägen, Stockholm, Sweden.InDex Pharmaceuticals, Tomtebodavägen, Stockholm, Sweden.InDex Pharmaceuticals, Tomtebodavägen, Stockholm, Sweden.InDex Pharmaceuticals, Tomtebodavägen, Stockholm, Sweden.First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31630153

Citation

Schmitt, Heike, et al. "The TLR9 Agonist Cobitolimod Induces IL10 Producing Wound Healing Macrophages and Regulatory T Cells in Ulcerative Colitis." Journal of Crohn's & Colitis, 2019.
Schmitt H, Ulmschneider J, Billmeier U, et al. The TLR9 agonist cobitolimod induces IL10 producing wound healing macrophages and regulatory T cells in ulcerative colitis. J Crohns Colitis. 2019.
Schmitt, H., Ulmschneider, J., Billmeier, U., Vieth, M., Scarozza, P., Sonnewald, S., ... Atreya, R. (2019). The TLR9 agonist cobitolimod induces IL10 producing wound healing macrophages and regulatory T cells in ulcerative colitis. Journal of Crohn's & Colitis, doi:10.1093/ecco-jcc/jjz170.
Schmitt H, et al. The TLR9 Agonist Cobitolimod Induces IL10 Producing Wound Healing Macrophages and Regulatory T Cells in Ulcerative Colitis. J Crohns Colitis. 2019 Oct 20; PubMed PMID: 31630153.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The TLR9 agonist cobitolimod induces IL10 producing wound healing macrophages and regulatory T cells in ulcerative colitis. AU - Schmitt,Heike, AU - Ulmschneider,Julia, AU - Billmeier,Ulrike, AU - Vieth,Michael, AU - Scarozza,Patrizio, AU - Sonnewald,Sophia, AU - Reid,Stephen, AU - Atreya,Imke, AU - Rath,Timo, AU - Zundler,Sebastian, AU - Langheinrich,Melanie, AU - Schüttler,Jürgen, AU - Hartmann,Arndt, AU - Winkler,Thomas, AU - Admyre,Charlotte, AU - Knittel,Thomas, AU - Dieterich Johansson,Christine, AU - Zargari,Arezou, AU - Neurath,Markus F, AU - Atreya,Raja, Y1 - 2019/10/20/ PY - 2019/07/24/received PY - 2019/10/21/entrez PY - 2019/10/21/pubmed PY - 2019/10/21/medline KW - TLR9 KW - Ulcerative colitis KW - cobitolimod JF - Journal of Crohn's & colitis JO - J Crohns Colitis N2 - BACKGROUND AND AIMS: The topically applied Toll-like receptor 9 (TLR9) agonist cobitolimod is a first-in-class DNA-based oligonucleotide that 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 DSS-induced colitis model. Cultured blood and mucosal cells from UC patients were treated with cobitolimod and analyzed via microarray, qRT-PCR, ELISA and flow cytometry. Intestinal slides of cobitolimod treated UC patients were analyzed by immunohistochemistry. RESULTS: Cobitolimod administration markedly suppressed experimental colitis activity and microarrays analyses demonstrated mucosal IL10 upregulation and suppression of IL17 signaling 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 signaling 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: Our studies suggest that 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. SN - 1876-4479 UR - https://www.unboundmedicine.com/medline/citation/31630153/The_TLR9_agonist_cobitolimod_induces_IL10_producing_wound_healing_macrophages_and_regulatory_T_cells_in_ulcerative_colitis L2 - https://academic.oup.com/ecco-jcc/article-lookup/doi/10.1093/ecco-jcc/jjz170 DB - PRIME DP - Unbound Medicine ER -