ROCKing the Field of Intestinal Fibrosis or Between a ROCK and a Hard Place?

Rieder, Florian

doi:10.1053/j.gastro.2017.08.056

Cited by 8 publications

(6 citation statements)

References 20 publications

(22 reference statements)

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“…The role of Rho/ROCK/Actin/MRTF/SRF signaling, which is induced by TGF-β1 or matrix stiffness, has been revealed in intestinal fibrosis. 11,51,53,181 ROCK is activated in inflamed and fibrotic tissue in CD. The rectal delivery of a novel small molecule ROCK inhibitor (AMA0825) reversed the established intestinal fibrosis in 2 different murine models of fibrosis by diminishing the TGF-β1-induced MRTF and p38 MAPK activation and increasing autophagy in fibroblasts.…”

Section: Promising Anti-fibrotic Agents For Intestinal Fibrosismentioning

confidence: 99%

“…11 These findings indicate that combining anti-TNF with local AMA0825 therapy, should be evaluated further as a therapeutic strategy for treatment of stricturing CD. 181 Moreover, as mentioned in the previous section, neutralizing antibodies designed to block IL-36α/IL-36R signaling or TL1A/DR3 signaling, which are activated in patients with CD strictures, are now available for clinical studies and emerge as promising therapeutic strategies for intestinal fibrosis in CD. Anti-IL36R antibodies and anti-TL1A antibodies are currently tested in a clinical phase 2 trial in UC patients (NCT03482635 and NCT04090411, respectively).…”

Section: Promising Anti-fibrotic Agents For Intestinal Fibrosismentioning

confidence: 99%

“…The role of Rho/ROCK/Actin/MRTF/SRF signaling, which is induced by TGF-β1 or matrix stiffness, has been revealed in intestinal fibrosis [ 11 , 51 , 53 , 181 ]. ROCK is activated in inflamed and fibrotic tissue in CD.…”

Section: Future Perspectivesmentioning

confidence: 99%

“…In addition, combining AMA0825 with anti-TNF not only prevented fibrosis but also ameliorated inflammation, emphasizing the importance of combination therapy [ 11 ]. These findings indicate that combining anti-TNF with local AMA0825 therapy, should be evaluated further as a therapeutic strategy for treatment of stricturing CD [ 181 ]. Moreover, as mentioned in the previous section, neutralizing antibodies designed to block IL-36α/IL-36R signaling or TL1A/DR3 signaling, which are activated in patients with CD strictures, are now available for clinical studies and emerge as promising therapeutic strategies for intestinal fibrosis in CD.…”

Section: Future Perspectivesmentioning

confidence: 99%

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Fibrostenotic strictures in Crohn’s disease

2020

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reported in 85%-100% of cases 7,10 and fibrostenotic stricture is the most common indication for surgery in CD. 3,9 Surgical resection is related with major morbidity, higher costs, higher risk of unemployment, and poorer quality of life. 3,11,12 Although the introduction of biologics including anti-TNF, anti-integrin, and anti-interleukin (IL) has modified the disease course of CD in the short term, the long-term outcome of those drugs on the development of fibrostenosis and the need for surgery remains to be elucidated. 5 Fibrostenotic strictures were previously considered an inevitable and irreversible consequence of long-term inflammation in CD patients whose conditions are unresponsive to anti-inflammatory therapies. This paradigm has been changing rapidly due to recent advances in our understanding regarding the process of intestinal fibrosis and the introduction of promising candidates for targeted anti-fibrotic therapy. 1 This review aimed to provide a comprehensive overview of fibrostenotic strictures in CD, including mechanisms and factors that predict its progression, as well as diagnosis and treatment strategies. It also introduces promising anti-fibrotic agents for intestinal fibrosis and discuss the obstacles to be overcome in developing clinically available anti-fibrotic agents for CD stricture.

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Section: Promising Anti-fibrotic Agents For Intestinal Fibrosismentioning

confidence: 99%

Section: Promising Anti-fibrotic Agents For Intestinal Fibrosismentioning

confidence: 99%

Section: Future Perspectivesmentioning

confidence: 99%

Section: Future Perspectivesmentioning

confidence: 99%

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Fibrostenotic strictures in Crohn’s disease

2020

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“…In experimental colitis, ROCK inhibition reduced fibrosis by inhibiting myofibroblast accumulation, expression of profibrotic factors, and accumulation of fibrotic tissue without affecting clinical disease activity or histological inflammation-a similar disjunction between inflammation and fibrosis that we observed in our study. Notably, ROCK inhibition was effective at reducing both inflammation and fibrosis only in conjunction with anti-TNF treatment, which was suggested as an initial clinical application in humans: the combination of a novel anti-fibrotic small molecule with a proven anti-inflammatory www.nature.com/scientificreports/ biologic 49 . An attractive potential alternative, however, might be monotherapeutic targeting of TL1A, as it may impact downstream pathways relevant to intestinal fibrosis such as Rho signaling, as well as previously described inflammatory pathways, thereby providing simultaneous anti-inflammatory and anti-fibrotic effects.…”

Section: Discussionmentioning

confidence: 99%

628 - Direct Signaling of TL1A-DR3 on Fibroblasts Induces Intestinal Fibrosis In Vivo

Jacob¹,

Kumagai²,

Abraham³

et al. 2018

Gastroenterology

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Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease, modulating the location and severity of inflammation and fibrosis. TL1A expression is increased in inflamed mucosa and associated with fibrostenosing Crohn's disease. Tl1a-overexpression in mice causes spontaneous ileitis, and exacerbates induced proximal colitis and fibrosis. Intestinal fibroblasts express Death-receptor 3 (DR3; the only know receptor for TL1A) and stimulation with TL1A induces activation in vitro. However, the contribution of direct TL1A-DR3 activation on fibroblasts to fibrosis in vivo remains unknown. TL1A overexpressing naïve T cells were transferred into Rag −/− , Rag −/− mice lacking DR3 in all cell types (Rag −/− Dr3 −/−), or Rag −/− mice lacking DR3 only on fibroblasts (Rag −/− Dr3 ∆Col1a2) to induce colitis and fibrosis, assessed by clinical disease activity index, intestinal inflammation, and collagen deposition. Rag −/− mice developed overt colitis with intestinal fibrostenosis. In contrast, Rag −/− Dr3 −/− demonstrated decreased inflammation and fibrosis. Despite similar clinical disease and inflammation as Rag −/− , Rag −/− Dr3 ∆Col1a2 exhibited reduced intestinal fibrosis and attenuated fibroblast activation and migration. RNA-Sequencing of TL1A-stimulated fibroblasts identified Rho signal transduction as a major pathway activated by TL1A and inhibition of this pathway modulated TL1A-mediated fibroblast functions. Thus, direct TL1A signaling on fibroblasts promotes intestinal fibrosis in vivo. These results provide novel insight into profibrotic pathways mediated by TL1A paralleling its pro-inflammatory effects. Death Domain Receptor 3 (DR3; TNFRSF25) is the only know receptor for TL1A (TNFSF15) 1-3. This cytokinereceptor pair controls a vast array of cellular effects, including propagation of inflammatory functions, adaptive immune cell expansion, and regulation of cell development and apoptosis: DR3 can upregulate NF-KB-dependent anti-apoptotic proteins such as c-IAP2 4. Furthermore, it can promote T cell inflammatory responses and cytokine production 5-7. In contrast, DR3's developmental and regulatory functions include induction of FADD-and caspase-8-dependent apoptosis and thymic negative selection 8,9. These diverse functions are compounded by the variety of cells that can elaborate TL1A in response to multiple stimuli: dendritic cells/macrophages responding to bacterial and immune complexes; endothelial cells induced by IL-1β and TNFα; as well as lymphoid lineage cells 10-13. Pertaining to IBD, genetic variants of TNFSF15 show elevated TL1A host expression, and are associated with a severe Crohn's Disease (CD) phenotype that features intestinal fibrostenosis and need for surgery 14-16. Consistent with human IBD, TL1A transgenic mice develop spontaneous ileitis and intestinal collagen deposition that is exaggerated under colitigenic conditions and results in severe inflammation and fibrosis 17-19. Neutralizing anti-TL1A monoclonal antibodies attenuate these effects, reducing in...

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