ABSTRACT
Title
Nuclear Receptors and Control of Inflammation associated with Spinal Cord Trauma: Pathophysiological Relevance
Authors
E. Esposito1 and S. Cuzzocrea1,2
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina;
IRCCS Centro Neurolesi “Bonino-Pulejo”
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina;
IRCCS Centro Neurolesi “Bonino-Pulejo”
Abstract
Nuclear receptors are ligand-dependent transcription factorsthat regulate gene networks involved in controlling growth, morphogenesis, cellular differentiation, and homeostasis. Intense efforts are currently being directed at defining the biological roles and mechanisms of action of liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs).
PPARs function asreceptors for fatty acids and their metabolites while LXRsare receptors for certain derivatives of cholesterol. PPARs and LXRs activate gene expression by binding to specific DNA response elements in target genes as heterodimers with retinoidX receptors (RXR), which are themselves members ofthe nuclear receptor superfamily. PPARs and LXRs also negatively regulate transcriptional programs involved in the development of inflammatory responses in aligand-dependent manner by antagonizing the activities of othersignal-dependent transcription factors, such as NFκB. Interestingly, LXRs may have overlapping functions with PPARsin the negative control of the inflammatory response. Similar to what has been described for PPARs, LXR antagonizes the NFκ B pathway through a mechanism that is not completely understood. LXR-deficient mice exhibited enhanced responses to inflammatorystimuli, and LXR ligands reduced inflammation in murine modelsof contact dermatitis, atherosclerosis, infection, lung inflammation, and spinal cord injury.
Current studies are addressed to decode the differentialand overlapping roles of PPARs and LXRs in the control of inflammation and tissue injury associated with spinal cord trauma.
Pharmacological activation of PPARs and LXRs can be considered as a multi-faceted therapeutic target due to theiranti-inflammatory/antioxidant/anti-excitotoxic/pro-energetic profile, reported in some inflammatory-related disease.
Because of safety and limited data, PPAR and LXR agonists are not yet included in trauma-related treatment strategies.
PPARs function asreceptors for fatty acids and their metabolites while LXRsare receptors for certain derivatives of cholesterol. PPARs and LXRs activate gene expression by binding to specific DNA response elements in target genes as heterodimers with retinoidX receptors (RXR), which are themselves members ofthe nuclear receptor superfamily. PPARs and LXRs also negatively regulate transcriptional programs involved in the development of inflammatory responses in aligand-dependent manner by antagonizing the activities of othersignal-dependent transcription factors, such as NFκB. Interestingly, LXRs may have overlapping functions with PPARsin the negative control of the inflammatory response. Similar to what has been described for PPARs, LXR antagonizes the NFκ B pathway through a mechanism that is not completely understood. LXR-deficient mice exhibited enhanced responses to inflammatorystimuli, and LXR ligands reduced inflammation in murine modelsof contact dermatitis, atherosclerosis, infection, lung inflammation, and spinal cord injury.
Current studies are addressed to decode the differentialand overlapping roles of PPARs and LXRs in the control of inflammation and tissue injury associated with spinal cord trauma.
Pharmacological activation of PPARs and LXRs can be considered as a multi-faceted therapeutic target due to theiranti-inflammatory/antioxidant/anti-excitotoxic/pro-energetic profile, reported in some inflammatory-related disease.
Because of safety and limited data, PPAR and LXR agonists are not yet included in trauma-related treatment strategies.