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Mission Statement: The innate immune system in retinal degenerative diseases – from understanding to novel innovative therapies

Loss of vision due to inherited (e.g. retinitis pigmentosa) or multifactorial (e.g. age-related macular degeneration) retinal disease is a devastating and in most cases unstoppable prognosis and accompanied by large constraints in the life quality of affected patients. To date, the Retnet database (https://sph.uth.edu/retnet/) lists a total of almost 300 genes and loci linked with retinal degenerations. 25% of these genes are causative for the most frequent monogenic group of disorders, retinitis pigmentosa (RP). On the other hand, the leading cause of legal blindness in the elderly of industrialized nations today is age-related macular degeneration (AMD), a complex genetic disease. In contrast to RP, a multitude of genetic risk variants as well as environmental risk factors contribute to the development of AMD and ultimately loss of vision.

Microglial cells are the resident phagocytes of the central nervous system (CNS), including the retina, and play pivotal roles in innate immune responses and regulation of homeostasis in the healthy and degenerating CNS. Reactive microgliosis is a common hallmark of neurodegenerative diseases and chronic pro-inflammatory microglial reactivity negatively contributes to disease progression (Langmann, 2007). Previous research from our laboratory could demonstrate the important role of innate immune activation during early retinal pathogenesis (Weigelt et al., 2007). Interestingly, we and others could show that this early reactivity of microglial cells is broadly independent of the underlying genetic defect or cause of retinal degeneration (Karlstetter et al., 2010a, Ebert et al., 2009, Karlstetter et al., 2014b, Scholz et al., 2015b)   

Our laboratory therefore postulates that targeted microglia-directed immunotherapy could represent an early and feasible strategy to attenuate progression of a variety of retinal degenerative diseases (Karlstetter et al., 2015). Using various cell culture and animal models together with modern tools of molecular biology, we constantly aim to identify novel microglial activation biomarkers and suitable target structures for microglia-directed immunotherapy in degenerative diseases of the retina.

Our previous in vivo and in vitro analyses enabled us to identify and characterize two novel biomarkers for microglial reactivity in the retina: Activated Microglia Whey Acidic Protein (AMWAP) and the Translocator Protein (18 kDa) (TSPO) (Karlstetter et al., 2010b, Aslanidis et al., 2015, Karlstetter et al., 2014a).  Further, we could demonstrate successful therapeutic microglia modulation and neuroprotection in mouse models of hereditary and light-induced retinal degeneration using the natural compounds curcumin and docosahexaenoic acid (DHA), the antibiotic minocycline as well as Interferon-ß and a synthetic TSPO ligand (Ebert et al., 2009, Mirza et al., 2013, Scholz et al., 2015b, Luckoff et al., 2016, Scholz et al., 2015a).

By identifying, characterizing and therapeutically utilizing further key molecules of microglial reactivity during retinal degeneration we aim to contribute to the development of promising novel therapeutic approaches for the treatment of retinal inflammation and degeneration.

 

Microglial Interferon-ß signaling – road to AMD therapy?

Anti‐VEGF is presently the gold standard in the treatment of choroidal neovascularization in wet AMD. However, inhibition of angiogenesis alone does not affect the cellular immunological events underlying CNV and also fails to be effective in the more common dry form of AMD. Furthermore, VEGF inhibition may cause a number of severe retinal and systemic adverse events. Therefore, there is an urgent need for identifying alternative approaches to treat AMD that is based on the underlying immunological pathogenesis. Type 1 Interferon signaling through the Ifnar receptor is a critical pathway in innate immune activity. Further, therapeutic interferon-β (IFN-β) has potent immunomodulatory effects on microglia both in vitro, in animal models of multiple sclerosis as well as being used for multiple sclerosis treatment in humans.

Our laboratory is interested in the role of IFN- β and its receptor Ifnar in the context of microglia in retinal degenerations like AMD. Using the laser-induced choroidal neovascularization (CNV) model of wet AMD, we could already demonstrate pivotal effects of Ifnar/IFN‐β signaling in retinal microglia and macrophages. We could show an essential role of interferon‐β signaling in regulating immune cell reactivity and pathological angiogenesis. Loss of Ifnar1 triggered microglia/macrophage activation, vessel leakage, and choroidal neovascularization (CNV). In contrast, IFN‐β therapy attenuated retinal immune cell response and CNV development (Luckoff et al., 2016).Our findings indicate a key role for Ifnar signaling in retinal immune activation and the immunomodulatory potential of IFN‐β as a promising new strategy for future therapy approaches to control chronic inflammation in AMD.

 

Polysialic acids as novel immunotherapeutics in AMD

Age-related macular degeneration (AMD) is the main cause of visual impairment and legal blindness in the industrialized world as more than one third of the population over the age of 75 develops AMD. Late-stage disease can either manifest as geographic atrophy or neovascular AMD. The neovascular or wet form is treated with intravitreally injected drugs targeting vascular endothelial growth factor (VEGF). In contrast, thereis currently no approved drug treatment for geographic atrophy, which is the atrophic or dry form of the disease.

AMD is associated with chronic innate immune activation specifically involving the complement system as well as activation of phagocytes and production of reactive oxygen species (ROS). Sialic acid polymers on the glycocalyx of healthy neurons inhibit complement activation and prevent ROS production of human phagocytes by acting on the inhibitory sialic-acid-binding immunoglobulin-like lectin-11 (SIGLEC11) receptor, but the therapeutic potential in AMD has not yet been evaluated.  Using the humanized SIGLEC11 transgenic mouse model of laser-induced retinal damage, we investigate the therapeutic immunomodulatory potential of polysialic acids in age-related macular degeneration. Our experiments demonstrate potent prevention of retinal microglia and choroidal macrophage reactivity induced by laser coagulation. Furthermore, polysialic acids reduce retinal vascular leakage and deposition of the membrane attack complex (MAC) in this transgenic laser-damage animal model. These protective effects are mediated by two synergistic effects on the innate immune system: Firstly, polysialic acids prevent overt production and release of pro-inflammatory molecules from reactive phagocytes via human SIGLEC1. Secondly, polySia avDP20 directly interferes with activation of the alternative complement pathway.

These findings reveal modulation of inflammatory SIGLEC11 signaling by polysialic acid treatment as a novel promising therapy option for AMD, by inhibiting the damaging effects of innate immune activation.

 

Translocator protein 18 kDa (TSPO) in microglia reactivity and immunotherapy

The translocator protein (18 kDa) (TSPO) is a mitochondrial protein expressed in reactive glial cells and a biomarker for gliosis in the brain but has just recently entered the spotlight in retinal degeneration research (Karlstetter et al., 2014a, Scholz et al., 2015a). We could show strong upregulation of TSPO transcript and protein levels in reactive microglial cells in vitro, microglia of the aSMase-deficient, retinoschisin-deficient and white light-induced retinal degeneration mouse models as well as TSPO expression in microglia of the human retina (Karlstetter et al., 2014a, Dannhausen et al., 2015, Scholz et al., 2015a). These were the first reports of TSPO as a microglial reactivity marker and potential therapeutic target in the retina.

Since TSPO is selectively upregulated in pathologies of the CNS, in recent years growing interest in the use of specific TSPO ligands as a strategy to attenuate neuroinflammation has emerged. In this regard, we could show that the synthetic TSPO ligand XBD173 effectively suppresses pro-inflammatory microglial reactivity in vitro by modulating pro-inflammatory microglial gene expression, migration, proliferation, NO secretion, neurotoxicity, proliferation, morphology and phagocytic capacity as well as reducing the number of amoeboid alerted microglia in organotypic murine retinal explant cultures (Karlstetter et al., 2014a).
In a following study we could, for the first time, demonstrate TSPO-mediated immunomodulatory and neuroprotective effects of XBD173 in mouse models of bright light-induced acute retinal degeneration. Specifically, systemic XBD173 treatment inhibited accumulation or reactive amoeboid microglia in the subretinal space and reduced both pro-inflammatory gene expression and photoreceptor apoptosis (Scholz et al., 2015a).
In summary, we contributed the first reports of TSPO as a microglial biomarker and potential therapeutic target to attenuate neuroinflammation in retinal degeneration.

Current TSPO-related projects in our laboratory focus on unraveling the microglia-specific regulation and induction of TSPO expression in retinal health and disease as well as on investigating the underlying molecular mechanisms of TSPO-mediated immunomodulation and neuroprotection using in vitro reporter assays as well as conditional microglia-specific knock-out mice and the laser-induced retinal injury model.

 

The role of the complement system and microglia in AMD

The pathogenesis of age-related macular degeneration (AMD) is multifactorial including environmental influences like age and diet as well as genetic risk factors, which are mainly associated with the complement system (e.g. CFH, C3) and extracellular matrix biology (e.g. Htra1). Histological analyses of human AMD retinas revealed prominent innate immune activation and microglia reactivity. We could previously contribute to the identification of rare genetic AMD risk variants in genes of the complement system and reveal disturbed complement factor regulation in AMD retinas (Ersoy et al., 2014, Fritsche et al., 2016). We further observed prominent subretinal microglia reactivity in the Htra1 overexpressing mouse model, which exhibits pathological changes in Bruch’s membrane integrity (Vierkotten et al., 2011).

In ongoing projects we aim to thoroughly characterize innate immune processes in the retina of the Htra1 transgenic, CFH-deficient mouse model (Htra1 Tg/CFH-/-) of AMD. These analyses include characterization of retinal complement factor expression/regulation as well as detailed assessment of microglial phenotypes in situ, ex vivo and after transplantation into healthy retinas. In parallel, we are interested in the examination of human AMD patients in regards of systemic vs. ocular complement regulation and malondialdehyde as indicators for oxidative stress. Finally, we aim to correlate the presence of hyperreflective foci in AMD retinas with microglia reactivity and established AMD biomarkers to contribute to a better understanding of the role of complement in chronic innate immune activation in AMD.

 

The role of microglia in neuronal ceroid lipofuscinoses (NCL)

Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative lysosomal storage disorders affecting children characterized by vision loss, mental and motor deficits, spontaneous seizures and premature death. To date, there is no viable therapy for NCL. Early NCL symptoms include progressive visual impairment accompanied by microglial reactivity in the retina, leading to severe impairment of the life quality in affected children.

Our laboratory’s research focuses on the retinal pathophysiology as well as the development of innovative immunotherapies to assist in future NCL treatment. Using a mouse model for variant-late infantile NCL (CLN6 (nclf)) we could demonstrate a progressive retinal degenerative phenotype together with reactivity of microglia and Mueller cells. These events overlapped with a rapid loss of visual perception and retinal function. Interestingly, dietary supplementation of these animals with the anti-inflammatory natural compounds curcumin and docosahexaenoic acid (DHA) could ameliorate microgliosis and reduce retinal degeneration (Mirza et al., 2013). Our results suggest that microglial reactivity closely accompanies disease progression in the CLN6 (nclf) retina and both processes can be attenuated with dietary supplemented immunomodulatory compounds.

Current NCL-related projects in our laboratory investigate retinal innate immune activation in a mouse model of juvenile NCL including generation and characterization of human iPS-derived microglia from NCL patients. Immunomodulatory therapy approaches in these models will then enable us to contribute to the development of potential novel intervention strategies for this devastating disease.

 

Cone-rod homeobox (CRX) and the transcriptional network of photoreceptors

Photoreceptors are highly specialized cells required for phototransduction within the retina and thus crucial for visual perception. The development of retinal progenitor cells into differentiated, fully functional photoreceptors is majorly orchestrated by the key transcription factor cone-rod homeobox (CRX) and inherited retinal diseases are mainly caused by mutations in CRX-regulated photoreceptor-specific genes.

Using genome-wide chromatin immunoprecipitation data (CRX ChIP-seq), we could demonstrate that CRX directly controls expression of the majority of photoreceptor-specific genes in the retina, including most known disease genes (Corbo et al., 2010). Employing this genome-wide dataset together with state-of-the-art reporter assays including ex vivo/in vivo electroporation of living mouse retinas we and others could already identify a novel  retinitis pigmentosa gene (FAM161A)  as well as a novel photoreceptor gene regulator with important functions in retinal health and disease (SAMD7) (Langmann et al., 2010, Hlawatsch et al., 2013, Van Schil et al., 2016). We could further validate the CRX-mediated expression of a known retinal disease gene (KCNV2) (Aslanidis et al., 2014), as well as identify novel important players in the photoreceptor transcriptional network.

Our studies on the transcriptional regulation of photoreceptor cells enable us to gain insights into potential disease mechanisms of retinal degeneration and suggest future strategies of identifying and managing hereditary retinal dystrophies early on.

 

Function and pathophysiology of the retinitis pigmentosa gene FAM161A

Retinitis Pigmentosa (RP) describes a group of related hereditary retinal degenerative disorders, in which mutations in retina-specific genes cause loss of functional photoreceptors ultimately leading to blindness. Following a combined approach of homozygosity mapping and CRX ChIP-seq, we could previously identify loss-of-function mutations in the FAM161A gene as a cause for autosomal-recessive RP (Langmann et al., 2010). FAM161A expression is tightly regulated by the master photoreceptor transcription factor CRX as shown by organotypic reporter assays in explanted mouse retinas.

Functional studies by our group and collaborators revealed localization of FAM161A protein to the ciliary region, linking photoreceptor outer and inner segments, as well as important functions in microtubule-mediated intracellular protein trafficking (Zach et al., 2012). Accordingly, genetically modified mice lacking functional FAM161A protein show very early disorganization of photoreceptor outer segments accompanied by inflammatory microglial reactivity followed by complete loss of the light-sensitive photoreceptor cells by 6 months of age. Using high-resolution and electron microscopy, we could identify defects in the transportation of important photoreceptor proteins along the connecting cilium of photoreceptor cells as an underlying disease mechanism (Karlstetter et al., 2014b).

Our laboratory employs the valuable FAM161A-deficient ciliopathy model to gain further insight into photoreceptor function in health and disease as well as a tool for investigating novel gene-replacement and immunomodulatory therapies.

 

Regulation and function of the X-linked juvenile retinoschisis gene RS1

X-linked juvenile retinoschisis (RS) is a frequent cause of macular degeneration in early adolescent men and characterized by a splitting (schisis) of the inner retina leading to progressive vision loss. The the causative gene (RS1) at Xp22.2 encodes a retina-specific protein presumably involved in cell-cell interaction at membrane surfaces contributing to proper development and integrity of the retinal layers.

Using cell culture assays as well as reporter electroporation assays in living mouse retinas, we could show that retina-specific expression of RS1 is tightly regulated by the photoreceptor-specific transcription factor CRX (Langmann et al., 2008, Kraus et al., 2011). In a collaborative approach, combining biochemical, lipidomic and physiological analyses in vitro and in RS1-deficient mouse models, we could demonstrate that Retinoschisin interacts with the retinal Na/K-ATPase to ensure proper protein localization and function in photoreceptor and bipolar cell outer membranes (Friedrich et al., 2011). In a translational project, we could demonstrate effective attenuation of pro-inflammatory microgliosis as well as the degenerative phenotype in the RS1-deficient mouse model after dietary supplementation with the ω3 fatty acid docosahexaenoic acid (DHA) (Ebert et al., 2009).

Current projects utilize the rapid degenerative and neuroinflammatory phenotype of the RS1-deficient mouse model to characterize and identify novel markers for microglial reactivity as well as further therapeutic intervention strategies.

 

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