Photoaging: UV radiation-induced inflammation and immunosuppression accelerate the aging process in the skin

Inflammation Research - Excessive exposure of the skin to UV radiation (UVR) triggers a remodeling of the immune system and leads to the photoaging state which is reminiscent of chronological...     

NF-κB signaling as a putative target for ω-3 metabolites in the prevention of age-related macular degeneration (AMD)

Age-related macular degeneration (AMD) is the major reason of blindness of the elderly all over the world. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, the highly specialized region of the retina responsible for sharp and color visual acuity. Degeneration and cell death of retinal pigment epithelial cells (RPE) cause secondarily adverse effects on neural retina leading to visual loss. Most AMD patients cannot benefit from any treatment modalities. The prevalence of AMD is rising as a consequence of the aging of the population. As the RPE cells age, they are subject to continued oxidative stress and this believed to induce inflammation and progression of AMD. Interestingly, many clinical trials have revealed that dietary intakes of ω-3 fatty acids can reduce the risk of both early and late AMD, although their molecular targets in cellular signaling in AMD pathology are not understood. Recently, it has been proposed that the ω-3 fatty acid metabolites, resolvins and protectins, function as endogenous anti-inflammatory compounds. In this review, we propose that resolvins and protectins mediate their beneficial effects by preventing NF-κB signaling and this that may represent a new target for regulating the inflammatory responses in AMD.     

Siglec receptors and hiding plaques in Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease. One hallmark of this disease is the continuous increase in the numbers and size of aggregating amyloid plaques. The accumulation of extracellular plaques is an immunologically interesting phenomenon since microglial cells, brain-specific macrophages, should be able to cleanse the aggregating material from the human brain. Immunotherapy targeting β-amyloid peptides in plaques with antibodies represents a promising therapy in AD. Recent progress in pattern recognition receptors of monocytes and macrophages has revealed that the sialic acid-binding, immunoglobulin-like lectin (Siglec) family of receptors is an important recognition receptor for sialylated glycoproteins and glycolipids. Interestingly, recent studies have revealed that microglial cells contain only one type of Siglec receptors, Siglec-11, which mediates immunosuppressive signals and thus inhibits the function of other microglial pattern recognition receptors, such as TLRs, NLRs, and RAGE receptors. We will review here the recent literature which clearly indicates that aggregating amyloid plaques are masked in AD by sialylated glycoproteins and gangliosides. Sialylation and glycosylation of plaques, mimicking the cell surface glycocalyx, can activate the immunosuppressive Siglec-11 receptors, as well as hiding the neuritic plaques, allowing them to evade the immune surveillance of microglial cells. This kind of immune evasion can prevent the microglial cleansing process of aggregating amyloid plaques in AD.     

Alpha-lipoic Acid modulates heat shock factor-1 expression in streptozotocin-induced diabetic rat kidney

Increased oxidative stress and impaired heat shock protein (HSP) synthesis may contribute to diabetic nephropathy. The question of whether 8-week thiol antioxidant alpha-lipoic acid (LA) supplementation modulates HSP response and oxidative stress was studied in the kidney of streptozotocin-induced diabetic (SID) and nondiabetic rats. SID caused a histological mesangial expansion, tubular dilatation, and increased levels of transforming growth factor-beta (TGF-beta), a mediator of glomerulosclerosis. SID increased 4-hydroxynonenal (4-HNE) protein adduct formation, a marker of lipid peroxidation, and heme oxygenase-1 (HO-1), also a marker of oxidative stress. Moreover, SID increased the DNA-binding activity of heat shock factor-1 (HSF-1) and expression of heat shock protein 60 (HSP60). In contrast, LA supplementation partially reversed histological findings of glomerulosclerosis and decreased TGF-beta. LA also increased HSF-1 and decreased HO-1 protein expression, without affecting 4-HNE protein adduct levels. At the mRNA level, LA increased expression of HSF-1, HSP90, and glucose-regulated protein (GRP75) in both control and diabetic animals and HSP72 in SID rats. However, LA supplementation did not affect these HSPs at the protein level. These findings suggest that in addition to its antiglomerulosclerotic effects, LA can induce cytoprotective response in SID.     

Absence of collagen XVIII in mice causes age-related insufficiency in retinal pigment epithelium proteostasis

Collagen XVIII has the structural properties of both collagen and proteoglycan. It has been found at the basement membrane/stromal interface where it is thought to mediate their attachment. Endostatin, a proteolytic fragment from collagen XVIII C-terminal end has been reported to possess anti-angiogenic properties. Age-related vision loss in collagen XVIII mutant mice has been accompanied with a pathological accumulation of deposits under the retinal pigment epithelium (RPE). We have recently demonstrated that impaired proteasomal and autophagy clearance are associated with the pathogenesis of age-related macular degeneration. This study examined the staining levels of proteasomal and autophagy markers in the RPE of different ages of the Col18a1 ^?/? mice. Eyes from 3, 6–7, 10–13 and 18 months old mice were enucleated and embedded in paraffin according to the routine protocol. Sequential 5 μm-thick parasagittal samples were immunostained for proteasome and autophagy markers ubiquitin (ub), SQSTM1/p62 and beclin-1. The levels of immunopositivity in the RPE cells were evaluated by confocal microscopy. Collagen XVIII knock-out mice had undergone age-related RPE degeneration accompanied by an accumulation of drusen-like deposits. Ub protein conjugate staining was prominent in both RPE cytoplasm and extracellular space whereas SQSTM1/p62 and beclin-1 stainings were clearly present in the basal part of RPE cell cytoplasm in the Col18a1 ^?/? mice. SQSTM1/p62 displayed mild extracellular space staining. Disturbed proteostasis regulated by collagen XVIII might be responsible for the RPE degeneration, increased protein aggregation, ultimately leading to choroidal neovascularization.     

Hydroquinone predisposes for retinal pigment epithelial (RPE) cell degeneration in inflammatory conditions

In addition to hypoxia, inflammation is capable of inducing vascular endothelial growth factor (VEGF) expression in human retinal pigment epithelial (RPE) cells. Excessive levels of VEGF promote choroidal neovascularization and thereby contribute to the pathogenesis of wet age-related macular degeneration (AMD). Intravitreal anti-VEGF injections ameliorate pathological vessel neoformation in wet AMD but excessive dampening of VEGF can result in a degeneration of the RPE. In the present study, we induced VEGF production by exposing human ARPE-19 cells to the pro-inflammatory IL-1α and subsequently to hydroquinone, a component of tobacco smoke that is a major environmental risk factor for AMD. Effects were monitored by measuring the levels of VEGF and anti-angiogenic pigment epithelium-derived factor (PEDF) using an enzyme-linked immunosorbent assay (ELISA) technique. In addition, we measured the production of reactive oxygen species (ROS) using the 2′,7′-dichlorofluorescin diacetate (H2DCFDA) probe and studied the effects of two anti-oxidants, ammonium pyrrolidinedithiocarbamate (APDC) and N-acetyl-cysteine (NAC), on VEGF production. Cellular and secreted VEGF as well as secreted PEDF levels were reduced at all tested hydroquinone concentrations (10, 50, or 200 µM); these effects were evident prior to any reduction of cell viability evoked by hydroquinone. Cell viability was carefully explored in our previous study and verified by microscoping in the present study. APDC further reduced the VEGF levels, whereas NAC increased them. The 50 μM concentration of hydroquinone increased ROS production in ARPE-19 cells primed with IL-1α. Hydroquinone disturbs the regulatory balance of VEGF and PEDF in inflammatory conditions. These data support the idea that hydroquinone mediates RPE degeneration by reducing VEGF levels and may predispose to dry AMD since VEGF is as well important for retinal integrity.

     

Molecular mechanisms of retinal pigment epithelium damage and development of age‐related macular degeneration

Age‐related macular degeneration (AMD) is attributed to a complex interaction of genetic and environmental factors. It is characterized by degeneration involving the retinal photoreceptors, retinal pigment epithelium (RPE) and Bruch’s membrane, as well as alterations in choroidal capillaries. AMD pathogenesis is strongly associated with chronic oxidative stress and inflammation that ultimately lead to protein damage, aggregation and degeneration of RPE. Specific degenerative findings for AMD are accumulation of intracellular lysosomal lipofuscin and extracellular drusens. In this review, we discuss thoroughly RPE‐derived mechanisms in AMD pathology.