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Updated: Aug 18, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Hormone regulation of microglial cell activation: relevance to multiple sclerosis
Paul D Drew1, Paul D Storer, Jihong Xu
1Department of Neurobiology and Developmental Sciences-Slot 510, University of Arkansas for Medical Sciences, Shorey Building, Little Rock, 72205, USA. drewpauld@uams.edu
Abstract:
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of proteins. The role of PPARs in regulating the transcription of genes involved in glucose and lipid metabolism has been extensively characterized. Interestingly, PPARs have also been demonstrated to mediate inflammatory responses. Microglia participate in pathology associated with multiple sclerosis (MS). Upon activation, microglia produce molecules including NO and TNF-alpha that can be toxic to CNS cells including myelin-producing oligodendrocytes and neurons, which are compromised in the course of MS. Previously, we and others demonstrated that PPAR-gamma agonists including 15d-PGJ(2) are effective in the treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. PPAR-gamma modulation of EAE may occur, at least in part, by inhibition of microglial cell activation. Here, we indicate that 15d-PGJ(2) is a more potent inhibitor of microglial activation than thiazolidinediones, which are currently used to treat diabetes. Furthermore, 15d-PGJ(2) acts cooperatively with 9-cis retinoic acid, the ligand for the retinoid X receptor (RXR), in inhibiting microglial cell activation. This suggests that 15d-PGJ(2) and 9-cis RA inhibit cell activation through the formation of PPAR-gamma/RXR heterodimers. Interestingly, PGA(2), which like 15d-PGJ(2) is a cyclopentenone prostaglandin, but which unlike 15d-PGJ(2) does not bind PPAR-gamma, is a potent inhibitor of microglial cell activation. Collectively, these studies suggest that 15d-PGJ(2) inhibits microglial cell activation by PPAR-gamma-dependent as well as PPAR-gamma-independent mechanisms. The studies further suggest that the PPAR-gamma agonist 15d-PGJ(2) in combination with retinoids may be effective in the treatment of MS.
Insights
Peroxisome proliferator-activated receptors (PPARs) modulate microglial activation, a key factor in multiple sclerosis (MS). The PPAR-gamma agonist 15d-PGJ(2) shows promise for MS treatment, acting both dependently and independently of PPAR-gamma.
Area of Science:
- Immunology
- Neuroscience
- Pharmacology
Background:
- Nuclear hormone receptors, including Peroxisome proliferator-activated receptors (PPARs), regulate genes involved in metabolism and inflammation.
- Microglia activation contributes to central nervous system (CNS) pathology in multiple sclerosis (MS) by releasing toxic molecules.
- PPAR-gamma agonists, such as 15d-PGJ(2), have shown efficacy in experimental autoimmune encephalomyelitis (EAE), an MS animal model, potentially by inhibiting microglial activation.
Purpose of the Study:
- To investigate the potency of 15d-PGJ(2) in inhibiting microglial activation compared to existing therapies.
- To explore the synergistic effects of 15d-PGJ(2) with retinoids in modulating microglial activation.
- To elucidate the mechanisms underlying 15d-PGJ(2)'s inhibitory effects on microglial activation.
Main Methods:
- Comparative analysis of 15d-PGJ(2) and thiazolidinediones in inhibiting microglial activation.
- Assessment of 15d-PGJ(2) combined with 9-cis retinoic acid (RXR ligand) for synergistic effects.
- Evaluation of prostaglandin A2 (PGA(2)) effects on microglial activation, independent of PPAR-gamma binding.
Main Results:
- 15d-PGJ(2) demonstrated greater potency in inhibiting microglial activation than thiazolidinediones.
- 15d-PGJ(2) exhibited cooperative inhibition of microglial activation with 9-cis retinoic acid, suggesting PPAR-gamma/RXR heterodimer involvement.
- PGA(2), a non-PPAR-gamma-binding prostaglandin, also potently inhibited microglial activation, indicating PPAR-gamma-independent mechanisms.
Conclusions:
- 15d-PGJ(2) inhibits microglial activation through both PPAR-gamma-dependent and -independent pathways.
- The combination of 15d-PGJ(2) and retinoids may offer a novel therapeutic strategy for MS.
- Further research into PPAR-gamma modulation and its downstream effects is warranted for MS treatment development.
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