Aryl hydrocarbon receptor‐driven signals inhibit collagen synthesis in the gut

Abstract

Fibrostrictures (FS) are a major complication of Crohn's disease (CD). Pathogenesis of FS is not fully understood, but activation of fibroblasts and excessive collagen deposition are crucial in the development of FS. Here, we investigated the role of aryl hydrocarbon receptor (AhR) in intestinal fibrosis. AhR RNA and protein expression were evaluated in intestinal fibroblasts of CD patients and controls. CD fibroblasts were stimulated with TGF-β1 or TNF-α in the presence or absence of the AhR activator Ficz, an AhR antagonist CH223191, or a specific AhR-silencing RNA. In CD fibroblasts, TGF-β1 and TNF-α increased Col1A1, Col3A1 and α-SMA transcripts and collagen secretion and this effect was reduced by Ficz and upregulated by CH22319. TGF-β1 or TNF-α induced activation of p38 and ERK1/2 MAP kinases was decreased by Ficz and increased by CH223191. The inhibitory effect of Ficz on Map kinase activation and collagen induction was abolished by AhR silencing. To assess the role of AhR in vivo, mice with trinitrobenzene-sulfonic-acid induced colonic fibrosis were given Ficz or CH223191. Mice given either Ficz or CH223191 produced less or more collagen respectively as compared with control mice. Our results indicate that AhR is a negative regulator of profibrotic signals in the gut.

Differential Expression of the Aryl Hydrocarbon Receptor and Transforming Growth Factor Beta 1 in Chronic Rhinosinusitis with Nasal Polyps with Allergic Rhinitis

“…The AhR pathway is vital for tissue repair, including inflammation, angiogenesis, and ECM remodeling [16]. Recent studies have shown that AhR was associated with the remodeling process in many tissues, such as the gut [17], dermal fibroblasts [18], and lung cancer [19]. However, the role of AhR in tissue remodeling of CRS is unknown.…”

Co-treatments to Boost IDO Activity and Inhibit Production of Downstream Catabolites Induce Durable Suppression of Experimental Autoimmune Encephalomyelitis

“…Prompted by this prior work, we tested if AhR signaling mediated therapeutic responses to STING agonists. Mice were given the AhR antagonist drug CH223191 (CH) at optimal doses (5 mg/kg) shown to block AhR signaling effectively in mice (30,(33)(34)(35). CH treatments were administered daily from EAE onset (day 11).…”

The Role of Cytokines in the Fibrotic Responses in Crohn’s Disease

“…Signaling through AhR, a receptor for environmental toxins, can induce activation and proliferation of many cell types, such as fibroblasts ( 59 , 60 ). By selectively stimulating or inhibiting AhR on isolated fibroblasts from CD patients, Monteleone et al ( 61 ) have shown that AhR negatively regulates TNF-α- or TGF-β-driven collagen production, by affecting activation of NF-κB and Smad2/3, respectively. Moreover, they also demonstrated in vivo that specific stimulation of AhR in mice reduces the fibrosis associated with chronic long-term administration of TNBS in mice.…”