Role of the nuclear receptor subfamily 4a in mast cells in the development of irritable bowel syndrome

Abstract

The activation of mast cells (MCs) and mediator release are closely related to the pathophysiology of irritable bowel syndrome (IBS). However, the exact underlying mechanisms are still not completely understood. The nuclear receptor subfamily 4a (Nr4a) is a family of orphan nuclear receptors implicated in regulating MC activation, degranulation, cytokine/chemokine synthesis and release. Acute and chronic stress trigger hypothalamic-pituitaryadrenal axis (HPA) activation to induce the release of corticotropin-releasing hormone (CRH), resulting in MC activation and induction of the Nr4a family. Our newest data showed that Nr4a members were specially over-expressed in colonic MCs of the chronic water-avoidance stress (WAS)-induced visceral hyperalgesia mice, suggesting that Nr4a members might be involved in the pathophysiology of visceral hypersensitivity. In this review, we highlight the present knowledge on roles of Nr4a members in the activation of MCs and the pathophysiology of IBS, and discuss signaling pathways that modulate the activation of Nr4a family members. We propose that a better understanding of Nr4a members and their modulators may facilitate the development of more selective and effective therapies to treat IBS patients.

Keywords: AF-1, activation function-1; AP-1, activator protein 1; BMMCs, bone marrow-derived MCs; CGRP, calcitonin gene-related peptide; CRH-R, corticotropin-releasing hormone (CRH) receptor; CoREST, corepressor for element-1-silencing transcription factor; DBD, DNA-binding domain; FcεRI, high affinity IgE receptor Fc epsilon RI; HPA, hypothalamic-pituitaryadrenal axis; Hypothalamic–pituitaryadrenal axis; IBS, irritable bowel syndrome; IKK, inhibitor of nuclear factor kappa-B kinase; IL, interleukin; Irritable bowel syndrome; JNK, Jun-N-terminal kinase; LBD, ligand-binding domain; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MCs, mast cells; Mast cells; NBRE, nerve growth factor-induced clone B (NGFI-B) response element; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; NFAT, nuclear factor of activated T-cells; NOR1, neuron-derived orphan receptor 1; Nr4a, nuclear receptor subfamily 4a; Nuclear receptor subfamily 4a; NurRE, Nur response element; P2X7, P2X purinoceptor 7; PAR2, protease--activated receptor 2; PI3K, phosphatidylinositol 3-kinase; PKCα, protein kinase C alpha; RSK, ribosomal S6 kinase; RXR, retinoid X receptor; TNF, tumor necrosis factor; WAS, chronic water-avoidance stress; iNOS, inducible nitric oxide synthase.