Kyle S. Johnson

Introduction: MS is a chronic inflammatory autoimmune disease involving myelin-specific autoreactive T cells that cause episodic progressive demyelination of CNS neuronal axons^1,2. Release of IL-17 by TH17 cells is heavily implicated in the pathogenesis of MS via TGF-B and IL-6 stimulated production of the transcription factor RORyT, thus increasing TH17 differentiation and IL-17 production³. IL-6 is associated with MS progression via stimulation of TH17 cell differentiation and chronic inflammation⁴. Current treatments involving IV glucocorticoids, monoclonal antibodies, topoisomerase inhibitors, and pyrimidine synthesis inhibitors have minimal long-term success due to high toxicity potential⁵. Studies have shown low-fat diets supplemented with N-3 PUFAs to be associated with reduction of relapse rates and increased CNS remyelination^5,6. The anti-inflammatory properties of N-3 PUFAs have largely been attributed to their overall reduction of eicosanoids, but more recent studies have shown connections between the alteration of lipid membrane raft responsiveness in CD4 T cells to IL-6, thus reducing TH17 cell differentiation and inflammation^7-10. Better understanding of this mechanism was explored for potential alternative MS treatments. Methods: Pubmed MeSH search was used to examine the literature for relevant studies, many of which utilized the Fat-1 mouse model and an experimentally-induced autoimmune disease, such as NZBWF1 systemic lupus erythematous (SLE), collagen antibody-induced rheumatoid arthritis (RA), or experimental autoimmune encephalitis (EAE). Results were analyzed with respect to mechanistic relation to MS therapy. Results: SLE mice fed N-3 PUFAs were associated with greater remission rates than those fed N-6 or N-9 PUFAs¹¹. Fat-1 RA mice were associated with suppressed TH17 cell production of inflammatory factors IL-6 and IL-17¹². Several other studies showed FAT-1 mice to be associated with decreased dimerization between glycoprotein 130 (GP130) and IL-6, inhibiting TH17 differentiation via STAT 3 pathway inhibition, along with disrupted lipid raft signaling via clustering of lipid raft markers Lck(N10) and LAT(ΔCP)^7,13. EAE mouse model studies involving Bu Shen Yi Sui Capsules (BSYSC), peroxisome proliferator-activated receptor-y agonists (PPAR-y agonists), and mi-RNAs were all shown to have similar effects to those of N-3 PUFAs on IL-6 and TH17 cell differentiation^14-17. Combination of miR-26a and N-3 PUFAs may offer therapeutic potential for MS^17-19. Conclusions: Future EAE mice studies are needed to explore the potential use of N-3 PUFAs to target IL-6 mediated lipid raft-based signaling in TH17 cell differentiation to slow progression of autoimmune diseases like MS. Potential synergistic effects between these pre-existing alternative therapies and N-3 PUFAs should be explored, particularly BSYSC and miR-26a.

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