PPARδ deficient mice develop elevated Th1/Th17 responses and prolonged experimental autoimmune encephalomyelitis
Saravanan Kanakasabai1, Crystal C Walline, Sharmistha Chakraborty
1Neuroscience Research Laboratory, Methodist Research Institute, Indianapolis, IN, USA.
Abstract:
Multiple sclerosis (MS) is a neurological disorder that affects more than a million people worldwide. The etiology of MS is not known and there is no medical treatment that can cure MS. Earlier studies have shown that peroxisome proliferator-activated receptor (PPARs) agonists ameliorate MS-like disease in experimental allergic encephalomyelitis (EAE). In this study we have used PPARδ deficient mice to determine its physiological role in the regulation of CNS EAE and MS. We found that PPARδ(-/-) mice develop EAE with similar day of onset and disease incidence compared to C57BL/6 wild type mice. Interestingly, both male and female PPARδ(-/-) mice showed prolonged EAE with resistance to remission and recovery. PPARδ(-/-) mice with EAE expressed elevated levels of IFNγ and IL-17 along with IL-12p35 and IL-12p40 in the brain and spleen. PPARδ(-/-) mice also developed augmented neural antigen-specific Th1/Th17 responses and impaired Th2/Treg responses compared to wild type mice. These findings indicate that PPARδ(-/-) mice develop prolonged EAE in association with augmented Th1/Th17 responses, suggesting a critical physiological role for PPARδ in the remission and recovery of EAE.
Insights
Peroxisome proliferator-activated receptor delta (PPARδ) deficiency in mice prolongs experimental allergic encephalomyelitis (EAE), a model for multiple sclerosis. This suggests PPARδ is crucial for disease remission and recovery in EAE.
Area of Science:
- Neuroimmunology
- Molecular and Cellular Neuroscience
Background:
- Multiple sclerosis (MS) is a debilitating neurological disorder with unknown etiology and no cure.
- Peroxisome proliferator-activated receptor (PPAR) agonists have shown promise in ameliorating MS-like symptoms in experimental allergic encephalomyelitis (EAE).
Purpose of the Study:
- To investigate the physiological role of PPARδ in the regulation of central nervous system (CNS) EAE and MS.
- To determine the impact of PPARδ deficiency on EAE development, progression, and immune responses.
Main Methods:
- Utilized PPARδ deficient (PPARδ(-/-)) mice and wild-type (C57BL/6) control mice.
- Induced EAE in both groups and monitored disease onset, incidence, and severity.
- Analyzed immune cell populations and cytokine profiles (IFNγ, IL-17, IL-12p35, IL-12p40) in the brain and spleen.
Main Results:
- PPARδ(-/-) mice exhibited EAE with similar onset and incidence as wild-type mice.
- PPARδ(-/-) mice displayed prolonged EAE, with significant resistance to remission and recovery.
- Elevated levels of IFNγ, IL-17, IL-12p35, and IL-12p40 were observed in PPARδ(-/-) mice.
- Augmented Th1/Th17 responses and impaired Th2/Treg responses were noted in PPARδ(-/-) mice.
Conclusions:
- PPARδ(-/-) mice develop prolonged EAE, characterized by augmented Th1/Th17 responses.
- These findings highlight a critical physiological role for PPARδ in promoting remission and recovery from EAE.
- PPARδ signaling may represent a potential therapeutic target for managing MS.
