Lutein as a Modulator of Oxidative Stress-Mediated Inflammatory Diseases

Abstract

Lutein is a xanthophyll carotenoid obtained from various foods, such as dark green leafy vegetables and egg yolk. Lutein has antioxidant activity and scavenges reactive oxygen species such as singlet oxygen and lipid peroxy radicals. Oxidative stress activates inflammatory mediators, leading to the development of metabolic and inflammatory diseases. Thus, recent basic and clinical studies have investigated the anti-inflammatory effects of lutein based on its antioxidant activity and modulation of oxidant-sensitive inflammatory signaling pathways. Lutein suppresses activation of nuclear factor-kB and signal transducer and activator of transcription 3, and induction of inflammatory cytokines (interleukin-1β, interleukin-6, monocyte chemoattratant protein-1, tumor necrosis factor-α) and inflammatory enzymes (cyclooxygenase-2, inducible nitric oxide synthase). It also maintains the content of endogenous antioxidant (glutathione) and activates nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2 signaling-related antioxidant enzymes (hemeoxygenase-1, NAD(P)H: quinone oxidoreductase 1, glutathione-s-transferase, glutathione peroxidase, superoxide dismutase, catalase). In this review, we have discussed the current knowledge regarding the anti-inflammatory function of lutein against inflammatory diseases in various organs, including neurodegenerative disorders, eye diseases, diabetic retinopathy, osteoporosis, cardiovascular diseases, skin diseases, liver injury, obesity, and colon diseases.

Keywords: inflammation; lutein; reactive oxygen species.

Figure 1

The proposed mechanism by which lutein inhibits oxidative stress-induced inflammatory responses in the brain. ROS levels increase in severe traumatic brain injury and lipopolysaccharide-activated microglia. Lutein reduces ROS levels and inhibits ROS-mediated activation of NF-kB and expression of inflammatory mediators (IL-1β, IL-6, MCP-1, TNF-α, COX-2, iNOS) [37]. In lipopolysaccharide-activated microglia, lutein activates ERK, which phosphorylates Nrf2 and increases dissociation of Keap1 from the Nfr2/Keap1 complex. Thus, it promotes nuclear translocation of Nrf2, which forms a heterodimer with sMaf protein and binds to a regulatory region of DNA called ARE. It induces the expression of Nrf2- target antioxidant genes (HO-1, NQO1). These antioxidant enzymes reduce intracellular ROS levels, which suppresses inflammatory responses [38]. Thus, lutein prevents oxidative stress-mediated neuroinflammation. ARE, antioxidant response element; COX-2, cyclooxygenase-2; ERK, extracellular signal-regulated kinase; HO-1, hemeoxygenase-1; iNOS, inducible nitric oxide synthase; IL, interleukin; Keap1, kelch like ECH associated protein 1; MCP-1; monocyte chemoattratant protein-1; NF−κB, nuclear factor-κB; Nrf2, nuclear factor erythroid 2–related factor 2; NQO-1, NAD(P)H: quinone oxidoreductase 1; ROS, reactive oxygen species; sMaf, small Maf; TNF-α, tumor necrosis factor-α.

Figure 2

The proposed mechanism by which lutein inhibits oxidative stress-induced inflammatory responses in the eye. ROS levels increase in aged retina and lipopolysaccharide-stimulated retinal pigment epithelial cells. Lutein reduces ROS levels and inhibits ROS-mediated activation of STAT3 [7] and the expression of inflammatory mediators (IL-1β, IL-6, MCP-1, TNF-α) [7,49,57]. Thus, it prevents age-related macular degeneration. In addition, lutein prevents oxidative stress-mediated G2/M arrest and apoptosis in retinal pigmental epithelial cells [48] and cross-linking and degradation of lens proteins which prevents cataractogenesis [56]. IL, interleukin; MCP-1; monocyte chemoattratant protein-1; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; TNF-α, tumor necrosis factor-α.

Figure 3

The proposed mechanism by which lutein inhibits oxidative stress-induced inflammatory responses in bone. ROS levels increase in monosodium iodoacetate-induced osteoarthritis in primary chondrocyte cells and femur tissues of ovariectomized rats (osteoporosis model). Lutein reduces ROS levels and inhibits ROS-mediated activation of NF-kB and the expression of inflammatory mediators (IL-1β, IL-6, TNF-α, COX-2). Moreover, lutein increases dissociation of Keap1 from Nfr2/Keap1 complex and thus, promotes nuclear translocation of Nrf2, which forms a heterodimer with sMaf protein and binds to the regulatory region of DNA called ARE. It induces the expression of Nrf2- target antioxidant genes (HO-1, NQO1). These antioxidant enzymes reduce intracellular ROS levels, which suppresses inflammatory responses [58,59]. In addition, lutein inhibits osteoclast-specific marker NFATc1 in the bone of ovariectomized rats [59]. Thus, lutein prevents oxidative stress-mediated osteoarthritis and bone deterioration. ARE, antioxidant response element; COX-2, cyclooxygenase-2; HO-1, hemeoxygenase-1; IL, interleukin; Keap1, kelch like ECH associated protein 1; NF−κB, nuclear factor-κB; Nrf2, nuclear factor erythroid 2–related factor 2; NQO-1, NAD(P)H:quinone oxidoreductase 1; NFATc1, nuclear factor of activated T cells 1; ROS, reactive oxygen species; sMaf, small Maf; TNF-α, tumor necrosis factor-α.

Figure 4

The proposed mechanism by which lutein inhibits oxidative stress-induced inflammatory responses in vascular endothelial cells. ROS levels increase in vascular endothelial cells exposed to high concentrations of homocysteine (atherosclerosis model) or lipopolysaccharide. Lutein reduces ROS levels and inhibits ROS-associated activation of NF-kB and expression of inflammatory mediators (IL-1β, IL-6, MCP-1, TNF-α, ICAM-1) in endothelial cells [71,76]. Moreover, lutein inhibits ROS-induced vascular dysfunction (decreased nitric oxide and increased endothelin-1), and thus, prevents vasoconstriction [71]. ICAM-1, intercellular adhesion molecule 1; IL, interleukin; MCP-1; monocyte chemoattratant protein-1; NF−κB, nuclear factor-κB; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α.

Figure 5

The proposed mechanism by which lutein inhibits oxidative stress-induced inflammatory responses in the liver. ROS levels increase in hepatic tissues exposed to hepatotoxins such as ethanol or arsenic pollutant. Lutein reduces ROS levels and inhibits ROS-mediated activation of NF-kB and the expression of inflammatory mediators (IL-1β, IL-6, MCP-1, TNF-α, COX-2, iNOS). Moreover, lutein increases dissociation of Keap1 from Nfr2/Keap1 complex and thus, promotes nuclear translocation of Nrf2, which forms a heterodimer with sMaf protein and binds to the regulatory region of DNA called ARE. It induces the expression of Nrf2- target antioxidant genes (HO-1, NQO1, GST, SOD, glutathione peroxidase, catalase). These antioxidant enzymes reduce intracellular ROS levels, which suppresses inflammatory responses [92,95]. Thus, lutein prevents oxidative stress-mediated hepatotoxicity. ARE, antioxidant response element; COX-2, cyclooxygenase-2; GSH, glutathione; GST, glutathione-s-transferase; HO-1, hemeoxygenase-1; IL, interleukin; iNOS, inducible nitric oxide synthase; Keap1, kelch like ECH associated protein 1; NF−κB, nuclear factor-κB; Nrf2, nuclear factor erythroid 2–related factor 2; NQO-1, NAD(P)H:quinone oxidoreductase 1; NFATc1, nuclear factor of activated T cells 1; ROS, reactive oxygen species; sMaf, small Maf; SOD, superoxide dismutase; TNF-α, tumor necrosis factor-α.