Liver X receptor beta deficiency attenuates autoimmune-associated neuroinflammation in a T cell-dependent manner
Jeroen F J Bogie1, Tim Vanmierlo2, Jasmine Vanmol1
1Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium; University MS Center Hasselt, Pelt, Belgium.
Abstract:
The initiation and progression of autoimmune disorders such as multiple sclerosis (MS) is linked to aberrant cholesterol metabolism and overt inflammation. Liver X receptors (LXR) are nuclear receptors that function at the crossroads of cholesterol metabolism and immunity, and their activation is considered a promising therapeutic strategy to attenuate autoimmunity. However, despite clear functional heterogeneity and cell-specific expression profiles, the impact of the individual LXR isoforms on autoimmunity remains poorly understood. Here, we show that LXRα and LXRβ have an opposite impact on immune cell function and disease severity in the experimental autoimmune encephalomyelitis model, an experimental MS model. While Lxrα deficiency aggravated disease pathology and severity, absence of Lxrβ was protective. Guided by flow cytometry and by using cell-specific knockout models, reduced disease severity in Lxrβ-deficient mice was primarily attributed to changes in peripheral T cell physiology and occurred independent from alterations in microglia function. Collectively, our findings indicate that LXR isoforms play functionally non-redundant roles in autoimmunity, potentially having broad implications for the development of LXR-based therapeutic strategies aimed at dampening autoimmunity and neuroinflammation.
Insights
Liver X receptor alpha (LXRα) deficiency worsened experimental autoimmune encephalomyelitis, while LXR beta (LXRβ) deficiency protected against this multiple sclerosis model. LXRβ
Area of Science:
- Immunology
- Neuroscience
- Metabolic pathways
Background:
- Autoimmune disorders like multiple sclerosis (MS) involve cholesterol metabolism and inflammation.
- Liver X receptors (LXRs) regulate both cholesterol and immunity, making them potential therapeutic targets.
- The distinct roles of LXR isoforms (LXRα and LXRβ) in autoimmunity are not well understood.
Purpose of the Study:
- To investigate the specific roles of LXRα and LXRβ in experimental autoimmune encephalomyelitis (EAE), a model for MS.
- To determine how individual LXR isoforms influence immune cell function and disease progression in autoimmunity.
Main Methods:
- Utilized the experimental autoimmune encephalomyelitis (EAE) mouse model.
- Employed cell-specific knockout models to differentiate LXRα and LXRβ functions.
- Analyzed immune cell physiology using flow cytometry.
Main Results:
- LXRα deficiency exacerbated EAE pathology and severity.
- LXRβ deficiency conferred protection against EAE.
- Reduced EAE severity in LXRβ-deficient mice was linked to peripheral T cell changes, independent of microglia.
Conclusions:
- LXRα and LXRβ isoforms have opposing, non-redundant roles in autoimmune neuroinflammation.
- Targeting LXR isoforms may offer novel therapeutic strategies for MS and other autoimmune conditions.
- Understanding isoform-specific functions is crucial for developing effective LXR-based therapies.
