Principles behind SLE treatment with N-acetylcysteine

Abstract

Systemic lupus erythematous (SLE) is a multisystem chronic autoimmune disease in which disrupted molecular pathways lead to multiple clinical manifestations. Currently approved treatments include hydroxychloroquine, some immunosuppressive medications, and some biologics. They all come with a range of side effects. N-acetylcysteine (NAC) is an antioxidant that has shown potential benefits in SLE patients without having major side effects. The following review highlights the molecular mechanisms behind the therapeutic effect of NAC in SLE patients. A higher-than normal mitochondrial transmembrane potential or mitochondrial hyperpolarization (MHP) was found in lymphocytes from SLE patients. MHP is attributed the blocked electron transport, and it is associated with the depletion of ATP and glutathione and the accumulation of oxidative stress-generating mitochondria due to diminished mitophagy. Comprehensive metabolome analyses identified the accumulation of kynurenine as the most predictive metabolic biomarker of lupus over matched healthy subjects. Cysteine is the rate-limiting constituent in the production of reduced glutathione, and it can be replaced by its precursor NAC. Kynurenine accumulation has been reversed by treatment with NAC but not placebo in the setting of a double-blind placebo-controlled clinical trial of 3-month duration. Mitochondrial oxidative stress and its responsiveness to NAC have been linked to systemic inflammation, gut microbiome changes, and organ damage in lupus-prone mice. Given the unique safety of NAC and chronicity of SLE, the clinical trial of longer duration is being pursued.

Keywords: N-acetylcysteine; mechanistic target of rapamycin; mitochondrial hyperpolarization; systemic lupus erythematosus.

Figure 1.

NAC beneficial effects on molecular and organismal levels. Exposure to NO and/or depletion of glutathione causes MHP and oxidative stress. The glutathione precursor NAC replenishes glutathione and prevents MHP. mTOR is a sensor of MHP and causes alteration of intracellular signal transduction and T-cell lineage specification leading to autoantibody formation and subsequent development of SLE. mTOR is also activated outside the immune system and it thus mediates end-organ damage, including the kidney and the liver. NAC treatment has had therapeutic benefits in SLE as measured by diminished SLEDAI and BILAG scores and fatigue and improved cognitive dysfunction on the ADHD Self-Reported Scale. ADHD, attention-deficit/hyperactivity disorder; BILAG, British Isles Lupus Assessment Group; MHP, mitochondrial hyperpolarization; mTOR, mechanistic target of rapamycin; NAC, N-acetylcysteine; SLE, systemic lupus erythematosus; SLEDAI, SLE Disease Activity Index.