Lipoic acid treatment inhibits monocyte/macrophage function in MS
S Fiedler, J George, and S Salinthone. VA Portland Health Care System and OHSU, Portland, OR, 97239
Multiple Sclerosis (MS) is a disease of the central nervous system (CNS) that causes neurodegeneration throughout the CNS. While MS is a neuro-inflammatory disease, alterations in the peripheral immune system are well established. There is increasing evidence of cross-talk between the peripheral and central immune systems. Current FDA-approved MS disease-modifying therapies (DMTs) are effective only in the inflammatory relapsing stage of MS. There is a frustrating lack of DMTs that can alter the functional decline of progressive MS (PMS), and compliance with many DMTs is compromised by unfavorable routes of administration, side effects, risks, and high costs. Thus, there is a need for development of therapies that are low-cost and low-risk. Lipoic acid (LA) exhibits antioxidant and anti-inflammatory properties; supplementation reduces disease severity and T lymphocyte migration into the CNS in a murine model of MS, and administration in secondary progressive MS subjects reduces brain atrophy compared to placebo. The mechanism of action (MOA) of LA's efficacy is incompletely understood. The premise of our investigation is that LA has an initial effect in the periphery and a downstream effect in the CNS. These effects may be directly related to the function of immune cells implicated in the pathogenesis of MS (including monocytes and microglia), or to the movement of immune cells into the CNS through the blood brain barrier. Here, we determined the effects of LA on monocyte/macrophage function. We compared the migratory capacity of human monocytes from healthy control (HC) and relapsing-remitting MS (RRMS) subjects, with or without LA. Basal migration of monocyte-enriched PBMCs from RRMS subjects is significantly higher than HC cells. LA treatment significantly inhibits monocyte migration in both cohorts. We then determined if there is differential LA effects on monocytes vs M1 macrophages by measuring secretion of pro-inflammatory mediators. LA inhibited secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and prostaglandins (PG) E and I in both cell types. These findings indicate that LA may provide protection against MS by inhibiting monocyte/macrophage function.
This work is supported by the Dept. of Veterans Affairs Biomedical Laboratory Research & Development Service.
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