The Importance of the Retinoid X Receptor Alpha in Modulating Inflammatory Signaling in Acute Murine Colitis

Abstract

Background In order for vitamin D to signal and regulate inflammatory pathways, it must bind to its receptor (VDR) which must heterodimerize with the retinoid X receptor alpha (RXRα). Although the role that vitamin D signaling plays in the development and progression of colitis, a disease characterized by excessive inflammation, has been suggested, little research has been done on determining the role that RXRα plays in acute colitis development. Aims This study sought to determine the effects that reduced availability of RXRα would have on the development of acute murine colitis. Expression of inflammatory markers, VDR and RXRα were investigated to determine if the reduction in expression of RXRα in RXRα+/− mice would result in increased inflammatory signaling and receptor downregulation as compared to their wild-type littermates. Methods An acute murine model of colitis, the axozymethane (AOM) and dextran sulfate sodium (DSS) model was utilized in wild-type and RXRα+/− mice. Gross manifestations of colitis measured included weight loss and colitis score. Immunblots and real-time PCR were performed for inflammatory markers and receptor expression. Results RXRα+/− mice induced with AOM/DSS colitis demonstrated increased gene expression of Snail and Snail2, transcription factors downstream of inflammatory mediators, as compared to their wild-type littermates. Conclusions This demonstrates the importance of RXRα in regulating inflammation in acute colitis and also identifies RXRα expression as a new consideration when developing successful interventions for acute colitis due to the requirement of numerous receptors for RXRα.

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

“…Accumulating evidence has now revealed their active role in the modulation of inflammatory responses and immunity. Acute challenge with AOM/DSS induces colitis in RXRα heterozygous mice with increased inflammatory maker expression [77] , and RXRα is highly expressed in macrophages [7] . Consistent with this, certain anti-inflammatory agents serve as RXRα ligands, implying that RXRα may be an intracellular target that mediates the anti-inflammatory effects of these agents.…”

Nuclear Receptors Regulate Intestinal Inflammation in the Context of IBD

“…Especially the RXR/PPARγ heterodimers, which are permissive to activation by both PPARγ and RXR ligands, have been investigated in colitis models (200). Rxra +/− mice are highly sensitive to TNBS colitis and AOM/DSS colitis induction (Table 2B) (201). In the colon, the RXR ligand LG101305 is equally effective as PPARγ ligands in reducing intestinal inflammation during TNBS colitis.…”

A Combined Phytochemical and Network Pharmacology Approach to Reveal the Effective Substances and Mechanism of Eomecon chionantha Hance for the Treatment of Ulcerative Colitis

“…53 In azoxymethane/dextran sulfate sodium-induced RXRA +/-mice, the expression of RXRA in the intestinal tissues of RXRA +/-mice decreases compared with wild-type mice, accompanied by upregulation of two genes, Snail1 and Snail2, which are transcription factors downstream of inflammatory mediators. 54 Additionally, although UC presents a high risk of developing colorectal cancer, RXRA control can be beneficial in accelerating colitis-related colon cancer by promoting IL-6/STAT3 signaling. 55 Glycogen synthase kinase-3 beta (GSK3B), originally identified as a regulator of glycogen metabolism, is a serine/threonine kinase in mammalian eukaryotic cells that acts on numerous signaling proteins and transcription factors such as c-Jun, AP-1, β-catenin, CREB, and NF-κB to regulate cell differentiation, proliferation, survival, apoptosis, and inflammation.…”