Key Functions and Therapeutic Prospects of Nur77 in Inflammation Related Lung Diseases

Abstract

The transcription factor Nur77 belongs to the NR4A subfamily of nuclear hormone receptors. It features an atypical ligand-binding site that precludes canonical ligand binding, leading to the designation orphan nuclear receptor. However, recent studies show that small molecules can interact with the receptor and modulate its activity by inducing a conformational change in the Nur77 ligand-binding site. Nur77 expression and activation are rapidly induced by various physiological and pathologic stimuli. Once expressed, Nur77 initiates transcriptional activity and modulates expression of its target genes. Both in vitro and in vivo evidence shows that Nur77 dampens the immune response to proinflammatory stimuli, such as tumor necrosis factor-α, Toll-like receptor ligands, and oxidized lipids, primarily by suppressing NF-κB signaling. Although studies focusing on Nur77's role in lung pathophysiology are currently incomplete, available data support its involvement in the pathogenesis of lung diseases, including asthma, acute lung injury, and pulmonary fibrosis, and thus suggest a therapeutic potential for Nur77 activation in these diseases. This review addresses the mechanisms that control Nur77 as well as its known roles in inflammation-related lung diseases. Evidence regarding the therapeutic potential of Nur77-targeting molecules will also be presented. Although current knowledge is limited, additional research followed by clinical studies may firmly identify Nur77 as a pharmacologic target for inflammation-related lung diseases.

Figure 1

Mechanisms of Nur77's transcriptional activities. On induction by various stimuli, Nur77 modulates target gene expression by binding to specific DNA sequences in their promoters. As a monomer, it binds to the NGFI-B response element (NBRE). As homodimers or heterodimers with Nur-related factor 1 or neuron-derived orphan receptor 1, it binds to the Nur-response element (NurRE). As heterodimers with retinoid X receptors (RXRs), it binds to a sequence termed DR5. In addition, Nur77 can indirectly suppress gene activity by modulating activities of other proteins, such as members of the NF-κB family and the zinc finger transcription factor (TF) specificity protein 1 (Sp1). RE, response element.

Figure 2

Nur77-mediated regulation of inflammation and lung diseases. Inhaled irritants up-regulate proinflammatory signals, such as tumor necrosis factor (TNF)-α, IL-1β, oxidized lipids (OxLipids), and Toll-like receptors (TLRs), in airway cells, which, in turn, induce Nur77 expression. Once expressed, Nur77 suppresses production of various molecules [eg, adhesion molecules, cytokines, chemokines, matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), and extracellular matrix (ECM)] and cellular processes (eg, enhanced proinflammatory activities and phenotype, growth, and survival). Consequently, the extent of inflammatory responses and inflammation-induced tissue damage and remodeling, such as basement membrane (BM) and vasculature remodeling, are expected to remain under control. ICAM-1, intercellular adhesion molecule-1; IFN-γ, interferon-γ; MCP-1, monocyte chemoattractant protein-1; VCAM-1, vascular cell adhesion molecule-1.