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.

Graphical abstract

Fig. 1

Nr4a family members share common structure/function domains and are modulated by kinases. (A) Domain structure of Nr4a orphan nuclear receptors and similarities among Nr4a1, Nr4a2 and Nr4a3. Nr4a members contain a variable N-terminal region (AF-1), a conserved DNA-binding domain (DBD), a hinge region and a variable C-terminal region (LBD/AF-2). (B) Specific binding sequences for the Nr4a subfamily. Nr4a family members act as transcription factors by regulating the transcription of their target genes through binding as monomers to NBRE sequences, as homodimers or heterodimers to NurRE sequences, or heterodimers with RXR to DR-5 sequences. (C) Overview of the amino-acid sequence of Nr4a1 with known phosphorylation sites and associated kinases indicated (T = threonine, S = serine).

Fig. 2

Summary of the possible mechanisms of the Nr4a subfamily in FcεRI-mediated MC activation. The Nr4a gene expression or nuclear translocation is induced by FcεRI cross-linking in activated MCs via the PKC/ERK pathway and the calcineurin-NFAT pathway, which provokes cytokine/chemokine gene transcription. Furthermore, Nr4a1 could promote MC activation by inhibiting the LKB1/AMPK signal pathway following FcεRI cross-linking. In addition, Nr4a1 NR4a3 could also positively regulate MC activation and degranulation by facilitating both Syk and Fyn activations.

Fig. 3

Double immunofluorescence staining with Nr4a2 (red) or Nr4a3 (red) and tryptase (a marker of MCs, green) revealed extensive co-localization (yellow) of Nr4a2 or Nr4a3 and tryptase in the colonic MCs of WAS mice, compared with non-WAS mice (normal). Scale bar, 50 µm. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Summary of the possible role of the Nr4a subfamily in the development of IBS through brain-MC connection activation by stress. The exposure to stress leads to CRH release from HPA axis, which induced gastrointestinal MC activation and Nr4a expression, as well as subsequent the changes in visceral sensitivity, gastrointestinal secretion and permeability, local immune response and inflammation, gastrointestinal motility and local blood flow.