Microglia in Retinal Degeneration

Abstract

The retina is a complex tissue with multiple cell layers that are highly ordered. Its sophisticated structure makes it especially sensitive to external or internal perturbations that exceed the homeostatic range. This necessitates the continuous surveillance of the retina for the detection of noxious stimuli. This task is mainly performed by microglia cells, the resident tissue macrophages which confer neuroprotection against transient pathophysiological insults. However, under sustained pathological stimuli, microglial inflammatory responses become dysregulated, often worsening disease pathology. In this review, we provide an overview of recent studies that depict microglial responses in diverse retinal pathologies that have degeneration and chronic immune reactions as key pathophysiological components. We also discuss innovative immunomodulatory therapy strategies that dampen the detrimental immunological responses to improve disease outcome.

Keywords: chronic inflammation; immunomodulation; microglia; neuroprotection; retina.

Figure 1

Schematic representation depicting cellular cross-talk between retinal cells and microglia. Retinal cells constantly communicate with microglia via various soluble factors and receptors to restrain microglia from tissue damaging activation and maintain them in a quiescent protective state. The bidirectional communicational between microglia and Müller cells can act as a mediator of neuron-microglia crosstalk. Microglia derived factors may either induce or inhibit release of secondary factors from Müller cells. TGF-β, transforming growth factor beta; TSP-1, thrombospondin-1; SOM, somatostatin; DBI, diazepine binding inhibitor; TTN, triakontatetraneuropeptide; BDNF, brain derived neurotrophic factor; CTNF, ciliary neurotrophic factor; GDNF, glial cell line-derived neurotrophic factor; NT-3, neurotrophin-3; NGF, nerve growth factor; bFGF, basic fibroblast growth factor; LIF, leukemia inhibitory factor.

Figure 2

Schematic model depicting the immunomodulatory effects of neuronal polysialic acids on microglia. Healthy neuronal cells have an intact glycocalyx displaying a polysialic acid (PolySia) cap. The PolySia cap is recognized and bound by Siglec-11, an inhibitory ITIM-signaling receptor. This interaction between neuronal PolySia and Siglec-11 inhibits microglia activation and maintains retinal homeostasis. However, during pathological conditions, neuronal glycocalyx is altered, leading to degradation of sialic acid caps. The exposed neuronal glycocalyx is then opsonized by complement component C1q, leading to subsequent recognition by ITAM-containing complement receptor 3 (CR3) in microglia and activation of inflammatory signaling and ROS production. ITIM, immunoreceptor tyrosine-based inhibition motif; ITAM, immunoreceptor tyrosine-based activation motif.

Figure 3

Endogenous and exogenous TSPO ligands dampen microglial activation. During retinal pathophysiology, microglia upregulate TSPO expression while Müller cells simultaneously upregulate the production and secretion of the endogenous TSPO ligand DBI. Secreted DBI can subsequently be cleaved extracellularly into the biologically active product TTN. Extracellular DBI and TTN are taken up by microglia, and their binding to the TSPO receptor serves to limit the magnitude of microglial inflammatory responses. DBI, diazepine binding inhibitor; TTN, triakontatetraneuropeptide; TSPO, translocator protein 18 kDa.

Figure 4

Modulation of microglial inflammatory responses by IFN-β signaling. IFN-β ligation to its receptor complex, IFNAR, triggers activation of the associated tyrosine kinases JAK1 and TYK2 and the subsequent phosphorylation of STAT1, STAT2, and STAT3 transcription factors. Phosphorylated STAT1 and STAT2 can recruit IRF-9 to the form the trimolecular complex STAT1–STAT2–IRF9 (ISGF3). Phosphorylated STAT3, and ISGF3 translocate to the nucleus and induce the transcription of various interferon-stimulated genes including SOCS1 and SOCS3 as part of a negative feedback loop. SOCS1 and SOCS3 inhibit excessive signaling by pro-inflammatory cytokines via the JAK-STAT pathway. IFN-β can also non-canonically activate the PI3K–AKT–mTOR pathway and suppress microglial inflammatory responses. mTORC1, downstream of PI3K–AKT can phosphorylate and activate STAT3, thereby enhancing expression of SOCS3. Activation of AKT downstream of IFN-β-PI3 inhibits GSK-3 activity through phosphorylation, negatively regulating GSK-3 mediated inflammatory responses, and promoting IL-10 expression. JAK1, Janus kinase 1; TYK2, tyrosine kinase 2; STAT, signal transducer and activator of transcription; IRF9, interferon regulatory factor 9; PI3K, phosphoinositide 3-kinase; AKT, protein Kinase B; mTOR, mammalian target of rapamycin; GSK-3, glycogen synthase kinase 3.