Resveratrol Role in Autoimmune Disease-A Mini-Review

Abstract

Autoimmune diseases are still considered to be pressing concerns due the fact that they are leaders in death and disability causes worldwide. Resveratrol is a polyphenol derived from a variety of foods and beverages, including red grapes and red wine. Anti-inflammatory, antioxidant, and antiaging properties of resveratrol have been reported, and in some animal and human studies this compound reduced and ameliorated the progression of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, and type 1 diabetes mellitus. Thus, this review aims to summarize and critically analyze the role of resveratrol in the modulation of several organ-specific or systemic autoimmune diseases.

Keywords: autoimmunity; inflammation; organ-specific; resveratrol; systemic.

Figure 1

(A) cis-resveratrol; (B) trans-resveratrol.

Figure 2

Type 1 diabetes mellitus disease mechanism and resveratrol role. Islet resident dendritic cell (DC) uptake of beta cell antigens, presenting to naïve T cells, and promoting promoting T-helper 1 (Th1) differentiation will activate B lymphocytes that will produce autoantibodies against beta cells. Th1 will also activate macrophage and neutrophil migrations to the islet that will promote beta cell destruction by increasing ROS. Resveratrol acts by (A) inhibiting Th1 cell migration by binding to CCR6 and (B) forming a complex with insulin that increases its glucose intake. Resveratrol also acts via SIRT1 to inhibit apoptotic cell injury during oxidative stress and increases antioxidant capacity by reducing ROS. In addition, resveratrol also plays a role in restoring beta cells in the islets. CCR6: chemokine receptor 6; APC: antigen presenting cell; FoxO3a: forkhead box O3; MHC: major histocompatibility complex; RNS: reactive nitrogen species; ROS: reactive oxygen species; SIRT1: Sirtuin 1; TCR: T-cell receptor. This figure used elements from Servier Medical Art (www.servier.com).

Figure 3

Inflammatory bowel disease (IBD) mechanisms and resveratrol role. IBD develops via a change the intestinal mucosal barrier that leads to a process involving bacterial translocation and subsequent activation of immune cells. The activation of neutrophils and macrophages in the epithelium leads to the production of inflammatory mediators, such as ROS and TNF-α. Antigen recognition by naïve T lymphocytes induces the differentiation to Th1 and Th17 profiles in Crohn’s disease, and to TH2 and Th17 profiles in ulcerative colitis, with the release of inflammatory cytokines, especially TNF-α. Resveratrol is capable of acting on the inhibition of inflammatory cytokines and neutralizing ROS. COX2: cyclooxygenase-2; IFN-γ: interferon gamma; IL: interleukin; MHC: major histocompatibility complex; MPO: myeloperoxidase; NO: nitric oxide; ROS: reactive oxygen species; TCR: T-cell receptor; TNF-α: tumor necrosis factor alpha. This figure used elements from Servier Medical Art (www.servier.com).

Figure 4

Psoriasis disease mechanism and resveratrol role. Psoriasis begins with the release of cathelicidin peptide (LL37) and fragments of DNA, forming an immunocomplex that activates resident DC cells. These cells activate T lymphocytes primarily through the release of IL-23, promoting differentiation into Th17. IL-16 promotes differentiation into Th1. These cells produce three major cytokines—IL-17, IL-22 (produced by Th17), and IFN (produced by Th1)—that promote the proliferation of keratinocytes. Resveratrol acts in two ways: inhibiting the production of IL-17 and directly inhibiting the proliferation of keratinocytes. DC: dendritic cell; IFN: interferon; IL: interleukin; MHC: major histocompatibility complex; RNS: reactive nitrogen species; ROS: reactive oxygen species; TCR: T-cell receptor. This figure used elements from Servier Medical Art (www.servier.com).

Figure 5

Rheumatoid arthritis mechanism and resveratrol’s role. The pathophysiological mechanism of rheumatoid arthritis (RA) is mediated by environmental factors and susceptible gene interactions, and the immune response involves a sequence of events. (A) In the lymph node, antigen recognition occurs by naïve T lymphocytes, which are differentiated to Th2 and Th17, with subsequent activation of B cells, with increased autoantibody production; (B) in addition, the Th17 response increases with the pro-inflammatory cytokine, IL-17; (C) Synovial macrophages may stimulate angiogenesis, leukocyte and lymphocyte recruitment, fibroblast proliferation, and protease secretion, contributing to cartilage and bone destruction at the site of pannus formation. In addition, the increased cytokine production, especially TNF-α and IL-1, stimulates synoviocytes; (D) the synovial fibroblasts at the inflammatory site increase COX2/PGE2, and a decrease in SIRT1. Chondrocytes are also stimulated by synovial macrophages; (E) Macrophages increase the recruitment of neutrophils at the inflammatory site, by increasing the production of ROS and RNS and the activation of MPO and NF-κB. Resveratrol is able to act by reducing the production of autoantibodies, Th17 population, oxidative stress and NF-κB activation. Resveratrol also reduces COX2 and PGE2 expression and activates SIRT1, therefore improving the patient's clinical condition. COX2: cyclooxygenase 2; IL: interleukin; TNF-α: tumor necrosis factor alfa; MMP: metalloproteinases; MPO: myeloperoxidase; NF-κB: nuclear factor kappa B; PGE2: prostaglandin E2; ROS: reactive oxygen species; RNS: reactive nitrogen species; SIRT1: sirtuin 1. This figure used elements from Servier Medical Art (www.servier.com).

Figure 6

Amyotrophic lateral sclerosis mechanism and resveratrol therapy. TDP-43 accumulation in the motor neuron cytoplasm deregulates mitochondrial biogenesis and SOD1 function, increasing glutamate and free radicals in the cytosol. Microglia detect an abnormal cell and activate naïve T-cell differentiation in the Th1 pattern that releases cytokines (TNF-α, INF, IL-1, IL-2, IL-6, and IL-7). Resveratrol acts by activating SIRT1 and regulates its substrate expression, increases the SOD1 useful life, reduces ROS, and acts in mitochondrial biogenesis as an antioxidant and antiapoptotic. IFN: interferon; IL: interleukin; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; ROS: reactive oxygen species; SIRT1: sirtuin 1; SOD1: superoxide dismutase 1; TDP-43: TAR DNA-binding protein 43; TNF-α: tumor necrosis factor alpha. This figure used elements from Servier Medical Art (www.servier.com).

Figure 7

Summary of the pathogenesis of systemic lupus erythematosus (SLE) and resveratrol mechanisms of action. The immune dysregulation caused by environmental triggers and genetic predisposition leads to increased apoptosis. Decreased clearance causes recognition of self-antigens by the immune system, activation of B and T cells, and the production of self-antibodies. Those antibodies, mainly IgG, cause the formation of immune complexes that can lead to renal impairment in kidneys and vasculopathy and atheromatous plaque formation in blood vessels. Atheroma plaques are caused by the action of anti-oxidized low-density lipoprotein (LDL), which is very common in SLE, which leads to the decrease of ABCA1 and ABCG1 by a yet unknown mechanism. Resveratrol acts as an SIRT1 activator, inhibiting proliferation of B and T cells and antibody production and also increasing ABCA1 and ABCG1 levels. ABCA1: ATP-binding cassette transporter A1; ABCG1: ATP-binding cassette transporter G1; APC: antigen presenting cell; IL: interleukin; MHC: major histocompatibility complex; SIRT1: sirtuin 1; TCR: T-cell receptor; TNF-α: tumor necrosis factor alpha. This figure used elements from Servier Medical Art (www.servier.com).