Cellular Retinoic Acid Bioavailability Determines Epithelial Integrity: Role of Retinoic Acid Receptor α Agonists in Colitis

Abstract

The epithelial barrier is determined primarily by intercellular tight junctions (TJs). We have demonstrated previously that all-trans retinoic acid (atRA) plays an important role in forming functional TJs through a specific retinoic acid receptor (RAR)/ retinoid X receptor heterodimer in epithelial cells. However, the physiological relevance of retinoic acids (RAs) in maintaining the epithelial integrity remains to be examined. Here, we show that several types of RA, including atRA, promote the barrier function of epithelial TJs. Conversely, RA depletion in the cells by overexpressing CYP26s, cytochrome P450 enzymes specifically involved in the metabolic inactivation of RAs, induces an increase of permeability as measured by two differently sized tracer molecules, inulin and mannitol. This RA-mediated enhancement of barrier function is potentially associated with the increased expression of TJ-associated genes such as occludin, claudin-1, claudin-4, and zonula occludens-1. We also found that RAR␣ is a preferential regulator of the epithelial barrier in vitro. Studies of murine experimental colitis, which is characterized by increased gut permeability, reveal that RAR␣ stimulation significantly attenuates the loss of the epithelial barrier during colitis in vivo. Our results suggest that cellular RA bioavailability determines the epithelial integrity, because it is a critical regulator for barrier protection during mucosal injuries.

Expression of Retinaldehyde Dehydrogenase Enzymes in Mucosal Dendritic Cells and Gut-Draining Lymph Node Stromal Cells Is Controlled by Dietary Vitamin A

“…Remarkably, in addition to the inhibitory effect of RA on TLR responsiveness in DCs, RA has been shown to increase intestinal epithelial barrier function (60,61). Therefore, in the case of vitamin A deficiency, the intestinal barrier might be compromised, resulting in enhanced invasion of bacteria and enhanced exposure of DCs to TLR ligands.…”

All-transRetinoic Acid Inhibits Type 1 Diabetes by T Regulatory (Treg)-Dependent Suppression of Interferon-γ–Producing T-cells Without Affecting Th17 Cells

“…Supplementation of vitamin A to animals results in a decrease in serum pro-inflammatory cytokines, including tumor necrosis factor-␣ and IFN-␥, and an increase in the immunosuppressive cytokine IL-10 (12,13). However, the mechanisms underlying the role of vitamin A or ATRA treatment in tolerance induction regulating autoimmune disease development have not been fully elucidated (13)(14)(15)(16)(17). Additionally, it is not clear whether ATRA treatment can inhibit type 1 diabetes.…”

Retinoic Acid Facilitates Toll-Like Receptor 4 Expression to Improve Intestinal Barrier Function through Retinoic Acid Receptor Beta

“…Retinoic acid (RA) also plays a role in protecting the intestinal barrier, and cellular RA bioavailability has been shown to determine epithelial integrity [4]. Additionally, VA improves intestinal epithelial cell migration and proliferation and prevents Clostridium difficile toxin A challenge-induced reductions in transepithelial resistance (TER) [5].…”