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Inflammation is an adaptive response of the immune system to noxious insults to maintain homeostasis and restore functionality. The retina is considered an immune-privileged tissue as a result of its unique anatomic and physiologic properties. During aging, the retina suffers from a low-grade chronic oxidative insult, which sustains for decades and increases in level with advancing age. As a result, the retinal innate-immune system, particularly microglia and the complement system, undergoes low levels of activation (parainflammation). In many cases, this parainflammatory response can maintain homeostasis in the healthy aging eye. However, in patients with age-related macular degeneration, this parainflammatory response becomes dysregulated and contributes to macular damage. Factors contributing to the dysregulation of age-related retinal parainflammation include genetic predisposition, environmental risk factors, and old age. Dysregulated parainflammation (chronic inflammation) in age-related macular degeneration damages the blood retina barrier, resulting in the breach of retinal-immune privilege, leading to the development of retinal lesions. This review discusses the basic principles of retinal innate-immune responses to endogenous chronic insults in normal aging and in age-related macular degeneration and explores the difference between beneficial parainflammation and the detrimental chronic inflammation in the context of age-related macular degeneration.

SummaryFundus autofluorescence (AF) imaging by confocal scanning laser ophthalmoscopy has been widely used by ophthalmologists in the diagnosis/monitoring of various retinal disorders. It is believed that fundus AF is derived from lipofuscin in retinal pigment epithelial (RPE) cells; however, direct clinicopathological correlation has not been possible in humans. We examined fundus AF by confocal scanning laser ophthalmoscopy and confocal microscopy in normal C57BL/6 mice of different ages.

Age-related macular degeneration (AMD) is a multi-factorial disease that is the leading cause of irreversible and severe vision loss in the developed countries. It has been suggested that the pathogenesis of dry AMD involves impaired protein degradation in retinal pigment epithelial cells (RPE). RPE cells are constantly exposed to oxidative stress that may lead to the accumulation of damaged cellular proteins, DNA and lipids and evoke tissue deterioration during the aging process. The ubiquitin-proteasome pathway and the lysosomal/autophagosomal pathway are the two major proteolytic systems in eukaryotic cells. NRF-2 (nuclear factor-erythroid 2-related factor-2) and PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1 alpha) are master transcription factors in the regulation of cellular detoxification. We investigated the role of NRF-2 and PGC-1α in the regulation of RPE cell structure and function by using global double knockout (dKO) mice. The NRF-2/PGC-1α dKO mice exhibited significant age-dependent RPE degeneration, accumulation of the oxidative stress marker, 4-HNE (4-hydroxynonenal), the endoplasmic reticulum stress markers GRP78 (glucose-regulated protein 78) and ATF4 (activating transcription factor 4), and damaged mitochondria. Moreover, levels of protein ubiquitination and autophagy markers p62/SQSTM1 (sequestosome 1), Beclin-1 and LC3B (microtubule associated protein 1 light chain 3 beta) were significantly increased together with the Iba-1 (ionized calcium binding adaptor molecule 1) mononuclear phagocyte marker and an enlargement of RPE size. These histopathological changes of RPE were accompanied by photoreceptor dysmorphology and vision loss as revealed by electroretinography. Consequently, these novel findings suggest that the NRF-2/PGC-1α dKO mouse is a valuable model for investigating the role of proteasomal and autophagy clearance in the RPE and in the development of dry AMD.

Photodynamic therapy (PDT) involves the administration of photosensitizer followed by local illumination with visible light of specific wavelength(s). In the presence of oxygen molecules, the light illumination of photosensitizer can lead to a series of photochemical reactions and consequently the generation of cytotoxic species. The quantity and location of PDT-induced cytotoxic species determine the nature and consequence of PDT. Much progress has been seen in both basic research and clinical application in recent years. Although the majority of approved PDT clinical protocols have primarily been used for the treatment of superficial lesions of both malignant and non-malignant diseases, interstitial PDT for the ablation of deep-seated solid tumors are now being investigated worldwide. The complexity of the geometry and non-homogeneity of solid tumor pose a great challenge on the implementation of minimally invasive interstitial PDT and the estimation of PDT dosimetry. This review will discuss the recent progress and technical challenges of various forms of interstitial PDT for the treatment of parenchymal and/or stromal tissues of solid tumors.

The eye and the brain are immunologically privileged sites, a property previously attributed to the lack of a lymphatic circulation. However, recent tracking studies confirm that these organs have good communication through classical site-specific lymph nodes, as well as direct connection through the blood circulation with the spleen. In addition, like all tissues, they contain resident myeloid cell populations that play important roles in tissue homeostasis and the response to foreign antigens. Most of the macrophage and dendritic cell (DC) populations in the eye are restricted to the supporting connective tissues, including the cornea, while the neural tissue (the retina) contains almost no DCs, occasional macrophages (perivascularly distributed), and a specialized myeloid cell type, the microglial cell. Resident microglial cells are normally programmed for immunological tolerance. The privileged status of the eye, however, is relative, as it is susceptible to immune-mediated inflammatory disease, both infectious and autoimmune. Intraocular inflammation (uveitis and uveoretinitis) and corneal graft rejection constitute two of the more common inflammatory conditions affecting the eye leading to considerable morbidity (blindness). As corneal graft rejection occurs almost exclusively by indirect allorecognition, host DCs play a major role in this process and are likely to be modified in their behavior by the ocular microenvironment. Ocular surface disease, including allergy and atopy, also comprise a significant group of immune-mediated eye disorders in which DCs participate, while infectious disease such as herpes simplex keratitis is thought to be initiated via corneal DCs. Intriguingly, some more common conditions previously thought to be degenerative (e.g. age-related macular degeneration) may have an autoimmune component in which ocular DCs and macrophages are critically involved. Recently, the possibility of harnessing the tolerizing potential of DCs has been applied to experimental models of autoimmune uveoretinitis with good effect. This approach has considerable potential for use in translational clinical therapy to prevent sight-threatening disease caused by ocular inflammation.

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The retina contains two distinct populations of monocyte-derived cells: perivascular cells (macrophages) and parenchymal cells (microglia), important in homeostasis, neuroinflammation, degeneration, and injury. The turnover of these cells in the retina and their repopulation in normal physiological conditions have not been clarified. Bone marrow (BM) cells from EGFP-transgenic mice were adoptively transferred into lethally irradiated normal adult C57BL/6 mice. Eight, 14, and 26 weeks later mice were sacrificed and retinal flatmounts were prepared. Retinal microglia were identified by F4/80, CD45, and Iba-1 immunostaining. BrdU was injected into normal mice for 3-14 days and cell proliferation was examined by confocal microscopy of retinal flatmounts. Few (6.15 +/- 2.02 cells/retina) BrdU(+) cells were detected and of these some coexpressed CD11b (1.67 +/- 0.62 cells/retina) or F4/80 (0.57 +/- 0.30 cells/retina). BM-derived EGFP(+) cells were detected by 8-weeks post-transplantation. By 6 months, all retinal myeloid cells were EGFP(+). Consecutively, donor BM-EGFP(+) cells were demonstrated within the: (1) peripheral and juxtapapillary retina, (2) ganglion cell layer, (3) inner and outer plexiform layers, and (4) photoreceptor layer. EGFP(+) cells within the ganglion layer were amoeboid in shape and F4/80(high)CD45(high)Iba-1(high), whereas cells in the inner and outer plexiform layers were ramified and F4/80(low) CD45(low)Iba-1(low). Perivascular macrophages expressed less F4/80, CD45, and Iba-1 compared with parenchymal microglia. Our results suggest that BM-derived monocyte precursor cells are able to migrate across the BRB and replace retinal microglia/macrophages. The complete replacement of retinal microglia/macrophages takes about 6 months. In situ proliferation was predominantly of nonhemopoetic retinal cells.