The NR4A subfamily of nuclear receptors: potential new therapeutic targets for the treatment of inflammatory diseases

ABSTRACT

Introduction: Prolonged inflammatory response contributes to the pathogenesis of chronic disease-related disturbances. Among nuclear receptors (NRs), the orphan NR4A subfamily, which includes Nur77 (NR4A1), Nurr1 (NR4A2) and NOR1 (NR4A3), has recently emerged as a therapeutic target for the treatment of inflammation.

Areas covered: This review focuses on the capacity of NR4A receptors to counter-regulate the development of the inflammatory response, with a special focus on the molecular transrepression mechanisms.

Expert opinion: Recent studies have highlighted the role of NR4A receptors as significant regulators of the inflammatory response. NR4A receptors are rapidly induced by inflammatory stimuli, thus suggesting that they are required for the initiation of inflammation. Nevertheless, NR4A anti-inflammatory properties indicate that this acute regulation could be a protective reaction aimed at resolving inflammation in the later stages. Therefore, NR4A receptors are involved in a negative feedback mechanism to maintain the inflammatory balance. However, the underlying mechanisms are not entirely clear. Only a small number of NR4A-target genes have been identified, and the transcriptional repression mechanisms are only beginning to emerge. Despite further research is needed to fully understand the role of NR4A receptors in inflammation, these NRs should be considered as targets for new therapeutic approaches to inflammatory diseases.

KEYWORDS:

• Chemokines
• cytokines
• inflammation
• NF-κB
• NR4A
• transactivation
• transrepression

Article highlights

• Inflammation is an adaptive biological response to infection, injury or autoimmune processes that aims to restore tissue structure and function. While acute inflammation is considered to be a beneficial mechanism that returns tissue to homeostasis, prolonged inflammation is associated with the pathogenesis of chronic disease disturbances.

• NR4A orphan nuclear receptors are early-response genes recently involved in inflammatory processes. The three NR4A receptors are rapidly induced by pro-inflammatory stimuli and are all involved in the counter-regulation of the later stages of inflammation.

• Despite the role of the NR4A in the counter-regulation of the inflammatory response has been well stablished, the precise contribution of these molecules guiding inflammatory responses and outcomes could be cell specific, since in some cell types they show pro-inflammatory features.

• The molecular mechanisms through which NR4A receptors are involved in the counter-regulation of inflammation include the direct binding to NR4A-target gene promoters (transactivation) and mechanisms that are independent of their DNA-binding capacity (transrepression).

• The identification of structurally diverse compounds that regulate NR4A activity has opened the door to the potential exploitation of these NRs as a therapeutic approach to inflammatory diseases.

• Although the findings are promising, extrapolating them to a clinical setting remains elusive, since further development of new selective regulators for each NR4A is required. Additionally, assessment of the efficacy and safety of the new NR4A regulators is required before they can be considered appropriate for clinical use.

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Declaration of interest

M. Vázquez-Carrera has received grants from the Ministerio de Economía y Competitividad of the Spanish government [SAF2012–30708 and SAF2015-64146-R], as well as funding from CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM). CIBERDEM is an initiative of the Instituto de Salud Carlos III (ISCIII)-Ministerio de Economía y Competitividad. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.