The orphan nuclear receptor RORα is a negative regulator of the inflammatory response

Abstract

Retinoid-related orphan receptor α (RORα) (NR1F1) is a member of the nuclear receptor superfamily whose biological functions are largely unknown. Since staggerer mice, which carry a deletion in the RORα gene, suffer from immune abnormalities, we generated an adenovirus encoding RORα1 to investigate its potential role in control of the inflammatory response. We demonstrated that RORα is expressed in human primary smooth-muscle cells and that ectopic expression of RORα1 inhibits TNFα-induced IL-6, IL-8 and COX-2 expression in these cells. RORα1 negatively interferes with the NF-κB signalling pathway by reducing p65 translocation as demonstrated by western blotting, immunostaining and electrophoretic mobility shift assays. This action of RORα1 on NF-κB is associated with the induction of IκBα, the major inhibitory protein of the NF-κB signalling pathway, whose expression was found to be transcriptionally upregulated by RORα1 via a ROR response element in the IκBα promoter. Taken together, these data identify RORα1 as a potential target in the treatment of chronic inflammatory diseases, including atherosclerosis and rheumatoid arthritis.

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

“…ROR␣ has been implicated in anti-as well as proinflammatory responses, including the inhibition of NF-B signaling and induction of Th17 differentiation, respectively (9,60). The diminished inflammatory response in WAT of ROR␣ sg/sg (HFD) mice is consistent with reports showing reduced inflammatory responses in allergeninduced airway inflammation and inhibition of experimental encephalomyelitis in ROR␣ sg/sg mice (19,60).…”

Immunometabolism: Is it under the eye of the clock?

“…This could be in part due to less transcriptional activation of Bmal1, or via ROR␣'s ability to induce transcription of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (I B␣), limiting translocation of NF-B to the nucleus [137]. Once again we see the dynamic nature and multiple targets of the clock proteins and the importance of this system for metabolism and immunity.…”

Rorα, a pivotal nuclear receptor for Purkinje neuron survival and differentiation: From development to ageing

“…Interestingly, stimulation of peripheral macrophage s of Rora sg/sg mutants by lipopolysaccharide (LPS) induces an abnormally high amount of pro-inflammatory cytokines IL-1, IL-6 and TNFα (40). In addition, Rora sg/sg mice are more susceptible to LPS-induced airway inflammation in the lung (41), and RORα has been reported to inhibit inflammatory responses in vascular smooth muscle cells (42). The anti-inflammatory role of RORα might be mediated in some tissues through the direct transcriptional control of the I-κBα gene, an inhibitor of the NF-κB transcription factor (42).…”

“…In addition, Rora sg/sg mice are more susceptible to LPS-induced airway inflammation in the lung (41), and RORα has been reported to inhibit inflammatory responses in vascular smooth muscle cells (42). The anti-inflammatory role of RORα might be mediated in some tissues through the direct transcriptional control of the I-κBα gene, an inhibitor of the NF-κB transcription factor (42). Moreover, abnormal IL-1β cytokine production has been also described in the staggerer brain after peripheral LPS treatment (43), demonstrating a general condition of hyperexcitability which could increase the neurodegeneration.…”