Microglia-Targeted Pharmacotherapy in Retinal Neurodegenerative Diseases

Abstract

Microglial cells, members of the monocytic lineage, represent the resident immunocompetent cells of the central nervous system including the retina with its peculiarities like a double blood retinal barrier. Microglial cells invade the retina in response to naturally occurring neuronal death during embryonic development and remodelling. Resident microglial cells are extremely sensitive to changes in their microenvironment arising from either traumatic or chronic neurodegeneration, inproper wiring, hereditary diseases or infection and become rapidly activated. In their activated state, the cells undergo drastic morphological changes, upregulate a variety of receptors and secrete soluble factors, which contribute to recognition and phagocytotic cleareance of dying or malfunctioning neurons. In this review, we aim to summarise the current knowledge of microglial involvement in experimentally induced or naturally occurring retinal neurodegenerations with emphasising on mechanisms of microglia activation. Expanding on the mechanisms, we shall discuss on approaches to pharmacologically interfere with the microglial activation and neurophagy. The protagonistic role of these cells in the outcome of certain diseases may help designing microglial targeted treatments with potential benefit for neuronal survival and regeneration in clinically relevant conditions.

Lipocalin-type Prostaglandin D2 Synthase Protein Regulates Glial Cell Migration and Morphology through Myristoylated Alanine-rich C-Kinase Substrate

“…The expression and secretion of L-PGDS increased under inflammatory conditions in macrophages (20). In the CNS, glial cells often participate in inflammatory responses, and activated glial cells have been identified in a broad spectrum of neuroinflammatory and neurodegenerative disorders including Alzheimer disease (69), Parkinson disease (70), amyotrophic lateral sclerosis (71), multiple sclerosis (72), and inherited photoreceptor dystrophies (73). L-PGDS secreted under these inflammatory conditions in the CNS may mediate the phenotypic changes associated with glial activation.…”

Activation of Bone Marrow-Derived Microglia Promotes Photoreceptor Survival in Inherited Retinal Degeneration

“…14,23,25,28,32,33 Microglial activation in the retina provides an early response against infection, injury, ischemia, and degeneration. 33,34 In retinal degeneration, activated microglia migrate into the deeper retina with the expression of tumor necrosis factor-␣ before the onset of photoreceptor cell death, 23 suggesting that microglial activation may trigger neuronal cell death. On the other hand, microglia secrete neurotrophic factors and promote photoreceptor survival in a light-induced retinal degeneration model, 32 and promote vascular repair in an oxygen-induced retinopathy model.…”

Possible mechanisms of retinal function recovery with the use of cell therapy with bone marrow-derived stem cells

“…Another possible mechanism is that microglia secrete neurotrophic factors to promote residual cell survivel (22)(23) . In the light-induced retinal degeneration model, microglia secrete nerve growth factor or ciliary neurotrophic factor and modulate secondary neurotrophic factor expression in Muller glia, contributing to the protection of photoreceptor cells (22)(23)(24) .…”