Many advancements in the understanding of multiple sclerosis (MS) have been made through the use of laboratory models. One commonly used model is experimental autoimmune encephalomyelitis (EAE), a mouse model characterized by central nervous system (CNS) inflammation and demyelination, allowing for symptoms resembling some of the most prominent features of the human disease. Although the exact etiology of MS is still being investigated, experiments with EAE have shown that the NLRP3 inflammasome complex of the innate immune system is critical and necessary for disease development. The inflammasome complex can be assembled in all innate immune cells, including microglia and astrocytes in the CNS. Dysregulation of inflammasome activity can result in uncontrolled inflammation, which underlies many chronic diseases, and metabolic and autoimmune disorders such as MS. Our lab has shown that farnesol a 15-carbon organic sesquiterpene and primary alcohol, reduced EAE disease severity and onset and also decreased T-cell infiltration into the CNS. However, the mechanisms of its action have yet to be fully defined. Therefore, in-vitro work on murine macrophages is being conducted to investigate how farnesol may be potentially affecting the pathway of the inflammasome complex and providing this protection. Furthermore, since farnesol is a quorum-sensing molecule that impacts biofilm formation, other studies of ours are aimed at evaluating how farnesol affects the gut-brain axis and specifically the gut microbiome of EAE mice.
Multiple Sclerosis (MS) is an autoimmune disease that causes T-cells to attack and degrade the myelin sheath of neurons in the spinal cord and brain. Farnesol is synthesized by plants and mammals and has anti-inflammatory along with neuroprotective activities. We used the MOG35–55 induced c57BL/6 murine EAE (experimental autoimmune encephalomyelitis) model due to model’s neurodegenerative and inflammatory properties. We predicted that farnesol would protect against EAE and increase autoimmunity markers. We collected spinal cords and spleens for flow cytometry analysis at the end of the study. This study found that farnesol significantly reduced spinal infiltration of CD4+ T cells, and increased infiltration of Tregs compared to untreated mice. Interestingly the proportion of CD25+Foxp3+ was increased compared to untreated mice, and statistically significant compared to vehicle treatment. We did not observe significant changes in CD4+, or CD25+Foxp3+ frequencies in the spleens. FOL treatment showed significant increase in CD11b+F4/80+ monocyte-derived macrophages (MDM) and F4/80int granulocytes/monocytes. FOL also showed significant weight retention and reduction of disease severity compared to untreated. These findings show that farnesol helps mediate the invasion of CD4+ T cells in the EAE model. Future studies should study how farnesol affects T-cell activation and differentiation, along with affects on macrophages and dendritic cells. This work was supported in part by the National Institutes of Health (grant R15NS107743)
Farnesol (FOL) is a naturally-produced 15-carbon organic acyclic sesquiterpene alcohol (isoprenol) that acts as a potent blocker of neuronal voltage-gated Ca2+ channels (L- and N-type) and is found in the human brain. FOL has potent anti-oxidant and anti-inflammatory effects in vitro and is neuroprotective in a murine model of neurotoxicity. Because inflammation and neurodegeneration are mechanisms associated with CNS demyelinating diseases, we sought to determine whether FOL treatment would result in protection against experimental autoimmune encephalomyelitis (EAE). We compared the progression of EAE in MOG35–55 immunized female C57BL/6 mice treated orally with FOL (100 mg/kg/daily) emulsified in corn oil, versus vehicle-treated and untreated EAE mice. FOL significantly reduced the average clinical scores of EAE mice when compared to untreated mice and vehicle-treated mice. The protective effect was associated with a significant reduction of CD4+ T cell spinal cord infiltration in FOL-treated mice as assessed by flow cytometry. Although FOL’s mechanism of action remains to be known, we propose that FOL promotes protection against CNS inflammatory demyelination by promoting an anti-inflammatory effect. We compared pro-inflammatory and anti-inflammatory cytokine transcriptional levels in brain tissues of EAE mice and histological analysis of CD4+ T cell CNS infiltration and demyelination. The potential benefit of FOL nanoencapsulation in neuroprotection was explored. We demonstrate that there is a correlation between the reduced neuroinflammation and EAE severity observed in the context of FOL protection. Understanding the neuroprotective effects of FOL may provide insight to novel therapeutic approaches for MS.
The gut microbiome aids in immune, endocrine and neural system functions and development. A disruption in the homeostasis of normal intestinal microbiota, known as dysbiosis, can result in changes believed to lead to pathological pathways which may mediate the development and progression of autoimmune diseases such as multiple sclerosis (MS). When compared with healthy individuals, clinical evidence shows those with autoimmune diseases have distinct microbiota, and those with MS have altered concentrations of specific microbial taxa. Diet is a key modulator of the composition of the gut microbiota and the risk for MS is two-times greater in individuals who are obese during adolescence. Therefore, dietary interventions as a possible therapeutic to modulate the composition of the microbiome and thus reduce the incidence or severity of disease are a crucial next step and could be a breakthrough in the treatment of MS. In this chapter we discuss the most salient experimental and clinical studies that explore diet as a potential avenue to treat this devastating disease. Although promising results arise, further studies are needed to assess the exact mechanism by which the gut microbiota and diet are impacting disease occurrence and progression.
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