Lutein as a Modulator of Oxidative Stress-Mediated Inflammatory Diseases

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.


Introduction
Carotenoids are divided into two classes based on their chemical structure: the carotenes (hydrocarbons, such as β-carotene and lycopene) and xanthophylls (polar compounds that contain oxygen atoms in their molecules, such as lutein and its stereoisomer zeaxanthin) [1]. Lutein is the second most prevalent carotenoid in human serum and is synthesized only by plants. It is abundantly present in eggs and dark green leafy vegetables such as kale and spinach [2][3][4].
Lutein acts as an antioxidant and protects plants from photo-induced free radical damage [5]. Xanthophyll carotenoids modulate oxidative stress and regulate redox-sensitive intracellular signaling [6]. Ozawa et al. [7] suggested that lutein inhibited oxidative stressinduced triggering of inflammatory signaling pathways such as the activated signal transducer and activator of transcription 3 (STAT3) signaling pathway and IL-6 expression in the retina. Lutein preserves visual function by preventing degradation of the functional proteins, rhodopsin (a visual pigment) and synaptophysin (a synaptic vesicle protein that is altered in neurodegenerative diseases). Lutein treatment reduced the concentrations of nitric oxide (NO), tumor necrosis factor (TNF)-α, interleukin (IL)-6, prostaglandin (PG)E 2 , and monocyte chemoattractant protein (MCP)-1 in aqueous humor of mice with endotoxininduced uveitis [8]. Lutein treatment suppressed the development of choroidal neovascularization, which plays a critical role in the pathogenesis of age-related macular degeneration and inflammatory processes, including nuclear factor (NF)-κB activation and subsequent caudalis and upper cervical dorsal horn neurons. These regions relay information to higher pain centers about the location and intensity of pain stimulus. This study supports lutein as a potential therapeutic agent to reduce or prevent acute trigeminal inflammatory pain. Overall, dietary lutein may be beneficial in maintaining cognitive health and protecting against inflammation-induced neurodegenerative diseases. 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 lipopolysaccharideactivated 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-re- 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 lipopolysaccharideactivated 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.
There are two types of Nrf2 activators. Most Nrf2 inducers interact with cysteine residues of kelch like ECH-associated protein 1 (Keap1) by utilizing the electrophilic nature of the molecules and inactivating the Keap1 E3 ligase activity that targets Nrf2 for ubiquitindependent degradation. The other type of Nrf2 inducer is nonelectrophilic inducers, which interrupt the interaction between Keap1 and Nrf2 [40]. Lutein does not have electrophilic groups. Thus, lutein metabolites that possess electrophilic groups may react with Keap1. In another way, lutein may directly disturb the interaction between Keap1 and Nrf2. Further study should be performed to determine whether lutein metabolites are electrophiles to react with cysteine residues of Keap1.
Since ROS activate Nrf2 signaling and produce antioxidant enzyems as a defense mechansim in some cells [41], further detailed study is necessary to determine the mechanism of how lutein induces dissociation of Nrf2/Keap1 and increases nuclear translocation of Nrf2.
Shimazu et al. [42] suggested that lutein attenuated acute inflammation-induced nocifensive behavior and augmented nociceptive processing of spinal trigeminal nucleus caudalis and upper cervical dorsal horn neurons. These regions relay information to higher pain centers about the location and intensity of pain stimulus. This study supports lutein as a potential therapeutic agent to reduce or prevent acute trigeminal inflammatory pain. Overall, dietary lutein may be beneficial in maintaining cognitive health and protecting against inflammation-induced neurodegenerative diseases.

Eye Diseases
Lutein, as a component of macular pigment, protects the macula from photo-oxidative damage and enhances visual function [29]. Lutein is an ocular antioxidant that can quench both singlet oxygen and lipid peroxy radicals [43]. In addition, lutein inhibits activation of STAT3 and IL-6 expression in the retina [7]. Therefore, supplementation with lutein has been very effective for restoring ocular antioxidants of age-related maculopathy and AMD [44][45][46] Oxidative stress is an important factor in the pathogenesis of age-related macular degeneration; thus, anti-oxidative stress is a good marker for the prevention or treatment of age-related macular degeneration. Lutein is a very effective quencher of singlet molecular oxygen and lipid peroxy radicals. However, lutein gets oxidized to its corresponding radical cations in the process. These cations must be reduced to regenerate the original carotenoids, which thus, allows its use as an antioxidant [47]. Lutein reduced ROS levels and suppressed apoptosis by reversing G2/M phase arrest through activation of cyclin-dependent kinase 1 and cell division cycle 25C in retinal pigment epithelial cells exposed to hydrogen peroxide [48]. Bian et al. [49] showed that lutein suppressed lipopolysaccharide-stimulated production of IL-6 and TNF-α in both retinal pigmental epithelial cells and macrophages isolated from the peritoneum of age-related macular degeneration model mice.
Lutein treatment reduced the light-induced increase in local ROS levels and inhibited tight junction disruption, determined by zona occludens-1 immunostaining, in mice [50]. Lutein intake increased macular pigment optical density and visual contrast sensitivity Antioxidants 2021, 10, 1448 5 of 23 in 90 patients with atrophic age-related macular degeneration [51], suggesting the lutein intake-mediated improvement in visual function.
Human clinical trials reported that individuals receiving lutein/zeaxanthin supplements experienced less vision loss than the controls [52]. Ma et al. [53] showed that a 12-week lutein supplementation improved visual function in healthy subjects exposed to long-term computer display light. These studies show that a high intake of lutein may have beneficial effects on visual performance.
Cataracts occur due to the loss of lens transparency caused by the aggregation of lens crystallins [54]. The risk factors attributed to the onset of cataracts include aging, diabetes, exposure to UV light, hypertension, and oxidative stress [55]. ROS cause cross-linking and degradation of lens proteins, thereby initiating cataractogenesis [56]. Padmanabha and Vallikannan [57] showed that eicosapentaenoic acid and docosahexaenoic acid increased the anti-cataract activity of lutein. Lutein decreased the serum and lens malondialdehyde levels, and the serum eicosanoids (PGE 2 , leukotriene B 4 , and leukotriene C 4 ), C-reactive protein, and cytokines (TNF-α, IL1-β, and MCP-1), but increased the activities of antioxidant enzymes catalase, superoxide dismutase (SOD), and glutathione peroxidase in rats. They suggested that therapy with lutein, eicosapentaenoic acid, and docosahexaenoic acid for regulation of oxidative stress and inflammation to counter cataracts may be more effective.
The biological role of lutein in the retina and lens has not yet been well elucidated, but these findings suggest that dietary lutein supplementation may be beneficial for preventing age-related macular degeneration and other eye diseases by reducing oxidative stress. The proposed mechanism by which lutein inhibits oxidative stress-induced inflammatory responses in the eye is shown in Figure 2. and macrophages isolated from the peritoneum of age-related macular degeneration model mice.
Lutein treatment reduced the light-induced increase in local ROS levels and inhibited tight junction disruption, determined by zona occludens-1 immunostaining, in mice [50]. Lutein intake increased macular pigment optical density and visual contrast sensitivity in 90 patients with atrophic age-related macular degeneration [51], suggesting the lutein intake-mediated improvement in visual function.
Human clinical trials reported that individuals receiving lutein/zeaxanthin supplements experienced less vision loss than the controls [52]. Ma et al. [53] showed that a 12week lutein supplementation improved visual function in healthy subjects exposed to long-term computer display light. These studies show that a high intake of lutein may have beneficial effects on visual performance.
Cataracts occur due to the loss of lens transparency caused by the aggregation of lens crystallins [54]. The risk factors attributed to the onset of cataracts include aging, diabetes, exposure to UV light, hypertension, and oxidative stress [55]. ROS cause cross-linking and degradation of lens proteins, thereby initiating cataractogenesis [56]. Padmanabha and Vallikannan [57] showed that eicosapentaenoic acid and docosahexaenoic acid increased the anti-cataract activity of lutein. Lutein decreased the serum and lens malondialdehyde levels, and the serum eicosanoids (PGE2, leukotriene B4, and leukotriene C4), C-reactive protein, and cytokines (TNF-α, IL1-β, and MCP-1), but increased the activities of antioxidant enzymes catalase, superoxide dismutase (SOD), and glutathione peroxidase in rats. They suggested that therapy with lutein, eicosapentaenoic acid, and docosahexaenoic acid for regulation of oxidative stress and inflammation to counter cataracts may be more effective.
The biological role of lutein in the retina and lens has not yet been well elucidated, but these findings suggest that dietary lutein supplementation may be beneficial for preventing age-related macular degeneration and other eye diseases by reducing oxidative stress. The proposed mechanism by which lutein inhibits oxidative stress-induced inflammatory responses in the eye is shown in Figure 2.  [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 degrada- 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.
Lutein increased the formation of mineralized bone nodules by upregulating bone morphogenetic protein 2 expression and downregulating sclerostin expression in osteoblast cultures [60]. Bone morphogenetic protein 2 plays a critical role in osteoblast differentiation and new bone formation. Sclerostin has anti-anabolic effects on bone formation. IL-1-induced osteoclast differentiation and bone resorption were suppressed by lutein [61]. Four-week supplementation with lutein increased the femoral bone mass in growing mice by stimulating bone formation and suppressing bone resorption [61].
Epidemiological studies have found a positive correlation between bone mass and carotenoid intake [62]. Dietary total carotenoids, α-, β-carotene, and lutein, were associated with a low risk of hip fracture in men [63]. Since total oxidative/anti-oxidative status is related to bone mineral density in osteoporosis [64], the intake of a lutein-rich diet can improve bone mineral status and may reduce the risk of osteoporosis and fracture. In general, lutein may be beneficial to bone health. 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 pri- 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.
Lutein increased the formation of mineralized bone nodules by upregulating bone morphogenetic protein 2 expression and downregulating sclerostin expression in osteoblast cultures [60]. Bone morphogenetic protein 2 plays a critical role in osteoblast differentiation and new bone formation. Sclerostin has anti-anabolic effects on bone formation. IL-1induced osteoclast differentiation and bone resorption were suppressed by lutein [61].
Four-week supplementation with lutein increased the femoral bone mass in growing mice by stimulating bone formation and suppressing bone resorption [61].
Epidemiological studies have found a positive correlation between bone mass and carotenoid intake [62]. Dietary total carotenoids, α-, β-carotene, and lutein, were associated with a low risk of hip fracture in men [63]. Since total oxidative/anti-oxidative status is related to bone mineral density in osteoporosis [64], the intake of a lutein-rich diet can improve bone mineral status and may reduce the risk of osteoporosis and fracture. In general, lutein may be beneficial to bone health.

Cardiovascular Diseases
Lutein has been introduced as a potential candidate for atheroprotection. Dwyer et al. [65] investigated the effect of lutein on the development of early atherosclerosis using epidemiological study, in vitro study, and a mouse model. An epidemiological study showed that subjects with the highest level of serum lutein (0.42 µmol/L) showed 80% lesser arterial wall thickening than those with the lowest quintile of serum lutein (0.15 µmol/L). In a study on monocyte migration in a co-culture model of human intima, lutein inhibited lowdensity lipoprotein-induced migration of monocytes in a dose-dependent manner. Lutein supplementation reduced atherosclerotic lesion formation in model mice [65]. According to a study conducted in Beijing, which comprised 125 subjects with early atherosclerosis and 107 controls aged 45-68 years, serum levels of lutein were significantly lower in cases of early arteriosclerosis than in controls. Serum lutein was observed to be inversely related to carotid intima-media thickness, an index of arteriosclerosis. However, there was no significant difference in zeaxanthin and β-carotene levels between the cases and controls [66].
Inflammation induces multiple risk factors for atherosclerosis and its complications [67]. The development of atherosclerosis lesions is initiated by oxidized low-density lipoprotein, leading to endothelial dysfunction and increased monocyte and chemokine levels. Subsequently, increased levels of cytokines and chemokines maintain and amplify the inflammatory responses [68]. The extent of inflammatory infiltrates and their strategic location within the protective fiber were related to plaque rupture or thrombosis in patients with atherosclerosis [69]. Speicific inflammatory mediators such as adhesion meolecules and chemoattractant proteins are involved in the pathogenesis of atherosclerosis [70,71].
Oxidative stress is also an important factor of atherosclerosis-associated endothelial injury and inflammation. Wang et al. [71] showed the effect of lutein intervention on hyperhomocysteinemia-mediated atherosclerosis. This study reported that hyperhomocysteinemia decreased vasodilator nitric oxide (NO) level and increased endothelin-1 level, which is associated with vascular endothelial dysfunction, but these levels were reversed by lutein. Lutein intervention also inhibited hyperhomocysteinemia-induced oxidative stress and downregulated inflammatory factors such as NF-κB p65, TNF-α, and intercellular adhesion molecule 1 [71] (Figure 4). As hyperhomocysteinemia induces oxidative stress and endothelial dysfunction, it can be associated with cardiovascular disease [72,73]. In TNF-α-treated vascular endothelial cells, lutein treatments improved basic endothelial function with increased NO and decreased release of endothelin-1 through inhibition of NF-κB signaling [74]. These results supported the effect of lutein on vascular structure and function to prevent atherosclerosis development and progression.
Endothelial function is modulated by vasodilators and vasoconstrictors. Vasodilator NO deficiency results in general vasoconstriction and hypertension. Lutein prevents hypertension through various pathways, including its influence on NO synthesis and enhancement of antioxidant properties [75].
Individuals with a history of atherosclerosis showed higher blood concentrations of complement factors C3 and C3a than subjects who have no such a history. C3 forms a membrane attack complex through an alternate complement pathway, creating a hole or pore in the membrane that can kill pathogens or host cells. Lutein has been shown to reduce the levels of plasma complement factors, including membrane attack complex. Thus, lutein may prevent or reduce tissue oxidation and prevent activation of damaging complement factors in the blood, leading to atheroprotection and cardiometabolic health [78]. 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; TNFα, tumor necrosis factor-α. 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.
Lutein supplements reduced the levels of serum inflammatory cytokines (IL-6, MCP-1), low-density lipoprotein, and triglyceride, which play important roles in the development of early atherosclerosis in patients [70]. Accumulating evidence also suggests a protective effect of lutein on cardiovascular disease and coronary heart disease. Most patients with coronary artery disease have chronic low-grade inflammation. Clinical findings have reported an inverse association between serum levels of lutein and IL-6 in patients with stable angina. When peripheral blood mononuclear cells from patients with coronary artery disease were pretreated with lutein, followed by treatment of lipopolysaccharide, it lowered lipopolysaccharide-induced secretion of IL-6, IL-1β, and TNF, and downregulated IL-6, IL-1β, and TNF mRNA expression in a dose-dependent manner [76] (Figure 4). Among carotenoids, including oxygenated carotenoids (lutein, zeaxanthin, β-cryptoxanthin) and hydrocarbon carotenoids (α-carotene, β-carotene, lycopene), serum levels of oxygenated carotenoids were reduced in patients with coronary artery disease, which was correlated with a low level of high-density lipoprotein that increases the risk of coronary artery disease [77]. These results support the potential anti-inflammatory effects of lutein in patients with coronary artery disease.
Individuals with a history of atherosclerosis showed higher blood concentrations of complement factors C3 and C3a than subjects who have no such a history. C3 forms a membrane attack complex through an alternate complement pathway, creating a hole or pore in the membrane that can kill pathogens or host cells. Lutein has been shown to reduce the levels of plasma complement factors, including membrane attack complex. Thus, lutein may prevent or reduce tissue oxidation and prevent activation of damaging complement factors in the blood, leading to atheroprotection and cardiometabolic health [78].

Skin Diseases
Lutein reduced ROS formation following ultraviolet (UV) irradiation, thus prevented the photo-oxidative damage and reversed contact hypersensitivity reactions which were Antioxidants 2021, 10, 1448 9 of 23 suppressed by UVB in mice [79]. A human study showed that oral supplementation of lutein and zeaxanthin improved overall skin tone and induced skin-lightening effects, which may be due to their antioxidant activities [80]. UV radiation and UVB radiation stimulate immunosuppressive and oxidative stress-inducing mechanisms that contribute to skin cancer, photodermatoses, sunburn, and photoaging [81,82]. In a human study, lutein supplementation (lutein soft gel capsules containing 10 mg free lutein stabilized by 10% carnosic acid for 12 weeks) reduced the mRNA expression of intercellular adhesion molecule 1 and metalloproteinase-1, which are indicators of photodermatoses and photoaging [83]. These studies indicate that lutein has a protective effect against UV-induced skin damage. Dietary lutein provided protection against skin swelling and hyperplasia caused by UV exposure in hairless mice [84]. Furthermore, lutein intake inhibited UVB-induced skin swelling, reversed the inhibition of contact hypersensitivity, and decreased ROS generation following UV radiation exposure in mice [79]. These results suggest that lutein reduces UV-induced inflammation and immunosuppression. In addition, lutein inhibits transient receptor potential ankyrin 1 activation-induced neutrophil accumulation, leading to suppression of skin inflammation [10].
Palombo et al. [85] demonstrated that 12-week Oral administration of lutein (10 mg/day) and zeaxanthin (0.6 mg/day) reduced skin lipid peroxidation (malondialdehyde level) and exhibited photoprotective activity following UV irradiation. Balic and Mokos [86] showed that β-carotene, lycopene, lutein, and astaxanthin exhibit photoprotective effects by direct light-absorbing properties, scavenging ROS, and/or suppressing inflammation. They demonstrated that human subjects with a carotenoid-rich diet showed decreased sensitivity to UV radiation-induced erythema (photoprotective effects on skin) and enhanced skin elasticity and hydration, skin texture, wrinkles, and age spots (anti-aging effect on skin). Thus, dietary intake of lutein is important for maintaining skin health and functions.

Liver Injury
Alcoholic liver disease leads to steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Alcohol is metabolized to toxic metabolites that cause redox imbalance [87]. Oxidative stress mediates inflammatory responses of hepatic cells, such as disturbances in calcium homeostasis, activation of mitogen-activated protein kinases and redox-sensitive transcription factors (such as NF-κB), and apoptosis, leading to alcohol-induced liver injury [88][89][90]. Therefore, reducing oxidative stress is expected to ameliorate alcoholinduced liver damage.
Kim et al. [93] reported that in hypercholesterolemic guinea pigs, 12 week-supplementation of lutein [0.1 g lutein/100 g high cholesterol diets (0.25% cholesterol)] reduced hepatic free cholesterol and hepatic TNF-α levels by attenuating the DNA-binding activity of NF-κB, compared with the control group. Mai et al. [94] showed that lutein treatment (40 mg lutein/kg body weight/day) decreased iNOS levels in the liver of mice with Dgalactose-induced liver injury. A mouse model showed that lutein treatment alleviated arsenic pollutant-induced hepatotoxicity by increasing the levels of Nrf2 signaling-related antioxidant enzymes (NQO1, HO-1, and GST) and reducing ROS and malondialdehyde levels in the liver [95]. Thus, lutein may reduce oxidative stress and inflammatory responses by activating Nrf2 signaling and inducing Nrf2-target antioxidant enzymes in the liver, thereby protecting the liver against hepatotoxins ( Figure 5). hepatic free cholesterol and hepatic TNF-α levels by attenuating the DNA-binding activity of NF-кB, compared with the control group. Mai et al. [94] showed that lutein treatment (40 mg lutein/kg body weight/day) decreased iNOS levels in the liver of mice with Dgalactose-induced liver injury. A mouse model showed that lutein treatment alleviated arsenic pollutant-induced hepatotoxicity by increasing the levels of Nrf2 signaling-related antioxidant enzymes (NQO1, HO-1, and GST) and reducing ROS and malondialdehyde levels in the liver [95]. Thus, lutein may reduce oxidative stress and inflammatory responses by activating Nrf2 signaling and inducing Nrf2-target antioxidant enzymes in the liver, thereby protecting the liver against hepatotoxins ( Figure 5). 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.

Obesity
Obesity is caused by excess intake of energy-dense foods and low physical activity, and it is a major risk factor for chronic diseases such as type 2 diabetes mellitus, hypertension, cardiovascular diseases, and cancer [96,97]. The levels of oxidative stress and inflammatory factors correspond to the amount of adipose tissue [98]. In particular, visceral fat is linked with the risk of obesity-associated diseases because it is related to insulin resistance (IR) and increased the levels of inflammatory mediators MCP-1, IL-6, TNF-α, and C-reactive protein [99,100].

Obesity
Obesity is caused by excess intake of energy-dense foods and low physical activity, and it is a major risk factor for chronic diseases such as type 2 diabetes mellitus, hypertension, cardiovascular diseases, and cancer [96,97]. The levels of oxidative stress and inflammatory factors correspond to the amount of adipose tissue [98]. In particular, visceral fat is linked with the risk of obesity-associated diseases because it is related to insulin resistance (IR) and increased the levels of inflammatory mediators MCP-1, IL-6, TNF-α, and C-reactive protein [99,100].
Serum lutein and zeaxanthin levels were observed to be inversely related to serum CRP concentrations [101]. Interestingly, serum levels of lutein and zeaxanthin were found higher in Mexican American and African American children and adolescents than in White American children and adolescents, based on the data from the U.S. NHANES III (1988)(1989)(1990)(1991)(1992)(1993)(1994).
Gopal et al. [102] showed that the accumulation of lipid droplets was significantly decreased in lutein-treated 3T3-L1 cells. This study found that lutein downregulated CCAAT/enhancer-binding protein-α (CEBP-α) and peroxisome proliferator-activated receptor-γ (PPAR-γ) during the early stage of adipocyte differentiation, which repressed the phosphorylation of protein kinase B and ERK. Blocking the initial stages of differentiation reduced mature adipocyte development and lipid accumulation.
Several studies have demonstrated a negative association between dietary lutein and serum lutein levels and adiposity [103,104]. Increased adiposity may also lead to inefficient delivery of lutein to the macula because adipose tissue acts as a sink for lutein [105,106]. Johnson [106] suggested that increased body fat induced oxidative destruction of endogenous lutein and changed lipoprotein profile, affecting the circulatory delivery of lutein to the macular of the eye.
In addition, the possible effects of lutein and zeaxanthin administration on lipid profile, oxidative stress, and inflammation pathways were investigated in a rodent model of high-fat diet-induced obesity [107]. Lutein and zeaxanthin supplementation reduced the levels of free fatty acids and oxidative stress markers (increased malondialdehyde levels and decreased antioxidant enzyme activities) in the retina of rats receiving a high-fat diet. These supplementations reduced the levels of vascular endothelial growth factor, NF-κB, and intercellular adhesion molecule 1 and enhanced Nrf2 and HO-1 protein expression in retinal tissues, which may have contributed to the alleviation of high fat diet-induced retinal injury. Collectively, lutein may be an effective treatment for retinal damage in obesity.

Colon Diseases
Ulcerative colitis is a long-term inflammatory condition of the colon and rectum [108]. Rana et al. [109] demonstrated that erythrocytes of patients with ulcerative colitis from northern India showed higher malondialdehyde levels but lower glutathione levels than healthy controls. In mice with dextran sulfate sodium-induced ulcerative colitis, lutein was supplemented in the form of dry hydroalcoholic extract of Tagetes erecta flowers (DHETE), and it reduced myeloperoxidase activity and levels of TNF and IL-6 [110]. Moreover, the extract reversed the reduction of glutathione levels and catalase activity and normalized the SOD and GST levels in the colon tissues. DHETE (300 mg/kg) prevented dextran sulfate sodium-induced weight loss, colon shortening, and morphological changes in rats. Further, lutein concentration in the DHETE was estimated at 8.2%. These studies showed the involvement of oxidative stress in the pathogenesis of ulcerative colitis, which was reversed by lutein treatment.
Rumi et al. [111] demonstrated lower levels of lutein and zeaxanthin in patients with Crohn's disease than in healthy subjects. Thus, intake of lutein and zeaxanthin may be beneficial for preventing the progression of Crohn's disease. Overall, lutein is expected to be a potential treatment for gastrointestinal disorders; however, large-scale human studies are needed to support the role of lutein in gastrointestinal protection in humans.

Diabetes
In the serum and retina of the diabetic population, low levels of lutein have been observed. Sahli et al. [112] found that a lutein-rich diet protects against the development of diabetic retinopathy in individuals with diabetes enrolled in a population-based cohort study. The protective effects of lutein on the retina have been reported in various studies. Wang et al. [113] showed that long-term lutein supplementation decreased retinal inflammation and functional deficits in early diabetic retinopathy using the genetic model for diabetic retinopathy. Another study examined the protective effect of lutein on hyperglycemia-mediated oxidative stress and antioxidant defense activity in retinal pigment epithelial cells [114]. This study reported that lutein treatment reduced ROS levels and reversed down-regulation of Nrf2 and antioxidant enzymes, SOD 2, HO-1, and catalase in APRE-19 cells. Lutein-induced activation of Nrf2 was linked to increased activation of regulatory proteins ERK and protein kinase B. These findings demonstrated that increasing concentration of lutein in the retina could protect the retina from diabetes-induced retinopathy. A systematic review and meta-analysis [115] showed that lutein might be beneficial for atherosclerosis and inflammatory markers, but there were inconsistent associations with blood pressure, adiposity, insulin resistance, and blood lipids. Although lutein can be a potential treatment for diabetes with its antioxidant properties, more preclinical and clinical studies are examined to confirm these above findings.

Conclusions
Due to its free radical scavenging activity, lutein reduces oxidative stress and inflammatory responses in various organs. Inflammatory stimuli and environmental stress, including UV light, may increase the production of ROS. Lutein reduces ROS levels and inhibits ROS-mediated activation of NF-kB and STAT3, and thus the expression of inflammatory mediators (IL-1β, IL-6, MCP-1, TNF-α, COX-2, iNOS). Lutein promotes Nrf2 activation and the expression of Nrf2-target antioxidant genes (HO-1, NQO1, GST, SOD, glutathione peroxidase, catalase) to reduce ROS levels. Since lutein reduces oxidative stress, it maintains the levels of endogenous antioxidants such as glutathione. The inhibitory effects on inflammatory signaling pathways and enhanced antioxidant activities of lutein may be the underlying mechanisms of protection against inflammation-related diseases.
Studies on lipopolysaccharide-stimulated microglia and high glucose-treated retinal pigment epithelial cells, lutein activates ERK, which may phosphorylate Nrf2 and Nrf2 activation induces production of Nrf2-driven antioxidant enzymes.
Lutein supplement reduces the levels of serum low-density lipoprotein and triglyceride, which play an important role in the development of early atherosclerosis in patients. In addition, lutein has light-absorbing and ROS-scavenging properties, which contribute to protection against UV light-induced skin damage; it suppresses transient receptor potential ankyrin 1-induced skin inflammation. Lutein reduces lipid droplet formation and downregulates CEBP-α and PPAR-γ during the early stage of adipocyte differentiation, which represses obesity-related inflammation. The effects of lutein on inflammatory responses in experimental models and epidemiological studies were summarized in Tables 1 and 2. -suppressed IL-1β, IL-6, and monocyte chemoattractant protein (MCP)-1 expression -reduced serum reactive oxygen species (ROS) levels -downregulated the expression of nuclear factor-κB (NF-κB) p65, and cyclooxygenase (COX) -2 -upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and endothelin-1 protein levels [37] LPS-induced neuroinflammation in mouse microglial cells      -serum level of high-density lipoprotein was directly related to serum levels of lutein + zeaxanthin -serum levels of C-reactive protein, an inflammation marker, were inversely related to serum levels of lutein + zeaxanthin [101] cross-sectional study in NHANES III 8808 U.S. adults, aged 20 and older with and without the metabolic syndrome -the age-adjusted concentration of lutein + zeaxanthin was lower in participants with metabolic syndrome than that of healthy control without the metabolic syndrome [103] a population-based, cross-sectional study 374 men, aged 40-80 -higher lutein+zeaxanthin intakes were associated with lower subcutaneous fat mass [104] Diabetes systemic review with meta analysis 71 relevant articles (including 387,569 participants) -there was an inconsistent association with higher dietary lutein intake and insulin resistance [115] In conclusion, lutein downregulates redox-sensitive inflammatory signaling pathways and inhibits the induction of inflammatory mediators. Therefore, it may prevent various inflammatory diseases, including neurodegenerative disorders, eye diseases including diabetic retinopathy, osteoporosis, cardiovascular diseases, skin diseases, liver injury, obesity, and colon diseases. Moreover, lutein exhibits tissue-specific actions, such as regulating lipid profiles in cardiovascular diseases, adipocyte differentiation in obesity, and skin function. Therefore, the consumption of lutein-rich foods may be beneficial in preventing oxidative stress-induced inflammatory diseases.
Author Contributions: H.K. conceived the outline and edited the paper; Y.J.A. performed the literature review, wrote the paper. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.

Conflicts of Interest:
The authors declare no conflict of interest.