Pivotal Role of Carbohydrate Sulfotransferase 15 in Fibrosis and Mucosal Healing in Mouse Colitis

Suzuki, Kenji; Arumugam, Somasundaram; Yokoyama, Junji; Kawauchi, Yusuke; Honda, Yutaka; Sato, Hiroki; Aoyagi, Yoshinobu; Terai, Shuji; Okazaki, Kazuichi; Suzuki, Yasuo; Mizumoto, Shuji; Sugahara, Kazuyuki; Atreya, Raja; Neurath, Markus F.; Watanabe, Kenichi; Hashiguchi, Taishi; Yoneyama, Hiroyuki; Asakura, Hitoshi

doi:10.1371/journal.pone.0158967

Cited by 50 publications

(50 citation statements)

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“…Specifically, a study has examined carbohydrate sulfotransferase 15 (CHST15) in gut inflammation 78 . CHST15 is a specific enzyme bio synthesizing chondroitin sulfate E that binds to vari ous pathogenic mediators and favours tissue fibrosis.…”

Section: Emerging Targets In Fibrosis and Tissue Remodellingmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

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528

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Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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Section: Emerging Targets In Fibrosis and Tissue Remodellingmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

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528

403

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“…STNM01 enhanced the mRNA expressions of E-cadherin and TGF-β induced EMT-counteracting molecule BMP-7, suggesting EMT-inhibiting effect (25). Reduced production of IL-6, MCP-1/CCL2 and collagen was observed in fibroblast cell lines by the treatment with STNM01.…”

Section: Mode Of Action Of Chst15 Inhibitor Stnm01 In Fibrosismentioning

confidence: 86%

“…STNM01 reduced the amount of CS/sulfated Glycosaminoglycan (GAG) in the human colon fibroblast and in in vivo disease models. The amount of E-unit of CS/sulfated GAG chain was selectively reduced in the human colon fibroblast (25).…”

Section: Mode Of Action Of Chst15 Inhibitor Stnm01 In Fibrosismentioning

confidence: 96%

“…STNM01 reduced the mRNA expressions of vimentin, α-SMA and Wnt3 by TGF-β-stimulated human fibroblast cell line as well as human colon cancer cell line, indicating that STNM01 inhibits the activation of fibroblasts from both resident fibroblasts and epithelial cells through epithelial mesenchymal transition (EMT) (25). STNM01 enhanced the mRNA expressions of E-cadherin and TGF-β induced EMT-counteracting molecule BMP-7, suggesting EMT-inhibiting effect (25).…”

Section: Mode Of Action Of Chst15 Inhibitor Stnm01 In Fibrosismentioning

confidence: 99%

“…STNM01 is a synthesized double stranded RNA oligonucleotide that selectively inhibits the expression of CHST15 gene (25,26). STNM01 (or experimental grade of CHST15 siRNA with the same sequence; hereafter we refer both as "STNM01") suppressed CHST15 mRNA in human colon and lung fibroblast cell lines in vitro and reduced the expression of CHST15 mRNA in the colon of mouse DSS colitis (25), the esophagus of pig esophageal stricture post ESD (27), the lung of mouse pulmonary fibrosis (28) and the heart of rat myocarditis (29).…”

Section: Mode Of Action Of Chst15 Inhibitor Stnm01 In Fibrosismentioning

confidence: 99%

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New endoscopic approach of anti-fibrotic therapy for inflammatory bowel disease

Suzuki

Yoneyama

2017

Ann. Transl. Med.

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Fibrosis continues to be paid a great attention in not only basic research but also clinical practice, especially for the development of novel therapeutics in various fibrotic diseases. However, there remain several obstacles to translation in developing anti-fibrosis therapy. The present review documents our translational practice from target discovery to first-in-patient studies in the development of anti-fibrosis therapy for inflammatory bowel disease (IBD). First topic is a target selection. We have focused on the target that has an ability to regulate multifactorial cascades of fibrosis. Carbohydrate sulfotransferase 15 (CHST15) synthesizes matrix proteoglycan that regulates various pathogenic mediators and contributes to tissue remodeling during injury. Small interfering RNA (siRNA) targeting CHST15 inhibited activation of fibroblasts in vitro and reduced fibrosis in vivo. Second topic is a clinically feasible application. We established a safe and novel pancolonic delivery of siRNA, which is achieved by direct injection to extracellular matrix (ECM) through endoscope. Third topic is an endpoint for both nonclinical and clinical studies. We have focused on tissue-specific findings for co-existence of fibrosis in ulcerative lesions in IBD and investigated whether the balance of mucosal healing (MH) and fibrosis, which is evaluated by endoscopy and histology respectively, can be used for study endpoints. Phase 1 clinical trial of STNM01, a synthesized CHST15 siRNA, by a single dose endoscopic submucosal injection for non-healer patients with Crohn's disease showed high rates of MH. Analyses of biopsy specimens revealed that STNM01 reduced CHST15 expression at local lesions, repressed pre-existing fibrosis and repaired the damaged crypts. Thus, blockade of multifactorial modulator CHST15 in ECM showed a potential to treat tissue remodeling and skew fibrosis toward mucosal repair. Our practice suggests that target-and tissue-specific findings-based strategy would be a key to translation in developing anti-fibrosis therapy.

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Silencing of tumoral carbohydrate sulfotransferase 15 reactivates lymph node pancreatic cancer T cells in mice

Suizu

Yamakawa

et al. 2023

Eur J Immunol

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Limited intratumoral T‐cell infiltration in pancreatic ductal adenocarcinoma (PDAC) is an obstacle to immunotherapy, yet the efficient approach to enhance tumor‐infiltrating T cells is not fully established. Here, we show that tumor‐specific knockdown of carbohydrate sulfotransferase 15 (CHST15), a tumor stromal proteoglycan‐synthetic enzyme, suppresses tumor growth in a T‐cell‐dependent manner in a murine model of PDAC. Silencing of tumoral CHST15 unexpectedly expanded CD4+ and CD8+ T cells in tumor draining LN (TDLN), leading to accelerated accumulation of EdU+ proliferating CD4+ and CD8+ T cells and granzyme B+ CD8+ T cells in the tumor. RNA expression analysis indicated that tumoral CHST15 knockdown (KD) downregulated matrix remodeling‐related genes, while upregulated anti‐tumor T‐cell activity‐related genes in both tumor and TDLN. CHST15 KD significantly diminished intratumoral and TDLN Ly6C/G+ myeloid‐derived suppressor cells prior to TDLN T‐cell expansion, suggesting that tumoral CHST15 remotely regulated myeloid‐derived suppressor cell mediated T‐cell suppression in the TDLN. Our findings illustrate a novel immunotherapeutic potential of tumoral CHST15 blockage by reactivating T cells in immune suppressive TDLN of PDAC.

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Pivotal Role of Carbohydrate Sulfotransferase 15 in Fibrosis and Mucosal Healing in Mouse Colitis

Cited by 50 publications

References 32 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

New endoscopic approach of anti-fibrotic therapy for inflammatory bowel disease

Silencing of tumoral carbohydrate sulfotransferase 15 reactivates lymph node pancreatic cancer T cells in mice

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