Authors - Yuan Xiangling, Chen Mei, Xu Heping

Editor-in-Charge - Wang Sizhen Editor - Retinal degenerative diseases are a type of disease that eventually leads to loss of visual function due to the degeneration of retinal neurons or neurovascular units, including age-related macular degeneration (AMD), retinitis pigmentosa (RP), diabetic retinopathy (DR) and glaucomatous retinopathy, among others
.

Inflammation plays an important role in the occurrence and development of retinal degenerative diseases, and how to prevent or delay the development of retinal degenerative degeneration by safely and effectively controlling inflammation is a hot topic
in current research.

Immunosuppressants such as steroids have been successfully used to treat macular edema caused by degenerative lesions of the retinal neurovascular units, but there is currently no effective treatment for degenerative lesions of retinal neurons
.

Therefore, an in-depth understanding of the immune response of retinal degenerative diseases, the promotion of the beneficial effects of inflammation and the suppression of its harmful effects are essential
for the treatment of retinal degenerative diseases.

On September 6, 2022, Professor Heping Xu of the Aier Institute of Optometry and Dr.
Mei Chen of the Wellcome-Wolfson Institute of Medicine at Queen's University of Belfast Medical School in the United Kingdom were invited to jointly publish a speech entitled "Immune response in retinal degenerative diseases – Time to rethink" at Progress in Neurobiology.
The latest cutting-edge discourse
.

Based on recent research advances in systems biology, cell biology and molecular biology, the authors propose to rethink the inflammatory response when retinal degenerative lesions are related, including the initiation, regulation and impact of inflammatory response on the occurrence and development of
the disease itself.

First, the authors divided retinal cells into primary cells (nerve cells) and supportive cells (glial cells, vascular related cells, retinal pigment epithelial cells
).

Primary functional cells mainly maintain visual function, while helper cells provide the most optimal living and working environment
for primary cells.

On this basis, the authors systematically elaborate the characteristics of immune responses in different types of retinal degeneration and their regulatory mechanisms according to whether the blood-retinal barrier (BRB) is destroyed and whether the retina accumulates fluid, systematically elaborates the characteristics of immune responses in different types of retinal degeneration and their regulatory mechanisms, and further explores the influence of genetic factors, aging and environmental/intestinal microbiome on the immune response of dry and wet retinal degenerative lesions.
Provides new ideas
for the development of strategies for the prevention and treatment of retinal degenerative diseases.

1.

The basic function of the retina is to obtain vision, and nerve cells are the key cells that convert the light signal entering the eye into a visual electrical signal, so it is called "primary cells", and other cells including glial cells, blood vessels-related cells and retinal pigment epithelium (RPE) provide a suitable and stable microenvironment for the survival of retinal nerve cells, collectively known as " Supportive cells" (Figure 1)[1].


Normal visual function requires that variables such as the number of different types of cells, the supply of oxygen and nutrients in the retina, the discharge of metabolic waste, and the volume and pH of the retinal interstitial fluid be kept within an appropriate range, and when these variables deviate from the steady-state range, an inflammatory response is initiated to maintain the homeostasis and visual function
.

Figure 1 Retinal cell type and visual function

(Source: Xu H et al.
, Prog Neurobiol, 2022)

The retina, as a nerve tissue, has immune privilege (IP), and its immune response is mainly done
by microglia and the complement system in the eye (rather than the circulating immune system).

Retinal neurons and RPE cells have a strong ability to regulate the activation of microglia and intraocular complement systems to ensure that the immune response is within the controllable range and to prevent inflammatory damage [2-3
].

In addition, genetic, aging, and environmental factors can also affect the inflammatory response of the retina, especially when the blood-retinal barrier is
disrupted.

Second, the immune response and its regulatory mechanism in "dry" and "wet" retinal degenerative lesions

In order to better understand the immune system's response to retinal degeneration and the effects of immune dysregulation on retinopathy, the authors propose to divide retinal degenerative variants into "dry" and "wet" types (Figure 2) according to whether the blood-retinal
barrier is damaged and leads to fluid overflow and accumulation in the retinal parenchyma (Figure 2).

Dry retinal degeneration manifests itself as a slow deterioration of visual function and progressive thinning of the retina, which leads to a reduced need for oxygen and nutrients in the retina, thereby reducing the burden on the
vascular system.

Typical dry retinal degeneration includes retinitis pigmented epithelial degeneration, retinopathy due to glaucoma, map atrophy age-related macular degeneration, and some pathological myopia caused by retinopathy [6
].

Wet retinal degeneration is characterized by damage to the blood-retinal barrier, fluid leakage leading to edema, damage to retinal neurons secondary to blood-retinal barrier dysfunction and retinal edema, and patients often present with acute vision loss
.

Diabetic retinopathy, wet AMD, uveitis, and retinal vein occlusion are all wet retinodegenerative pathologies [7-8
].

This classification of degenerative retinal lesions based on the function of the blood-retinal barrier helps to understand the immune response of the retina and to develop a rational disease management plan
.

1.
Immune response and its regulatory mechanism in dry retinal degenerative disease (Figure 2): Due to the relatively complete and functional blood-retinal barrier, the response of the whole immune system to dry retinal degenerative disease is limited
.

Inflammatory responses are usually performed by microglia, Müller cells, and intraocular complement systems, and their activation may be due to excessive damage to neurons (release of glutamine, ATP, etc.
, loss of immunosuppressive function, etc.
), susceptibility genes carried by patients (Cx3cr1, ApoE2, complement factor HY402H, etc.
), aging and environmental factors leading to disorders, causing excessive activation of microglia and complement, and promoting the development of degenerative retinal lesions [9-11]
。
Environmental factors (air, water, food, etc.
) can interfere with the retinal immune response by altering the gut microbiome, influencing the intraocular ecosystem through the gut-blood-eye pathway [12
].

2.
Immune response and its regulatory mechanism in wet retinal degenerative disease (Figure 2): Blood-retinal barrier dysfunction causes various variables in the retina to deviate from the steady state level, triggering inflammatory response
.

When damage to the blood-retinal barrier begins inside the retina (i.
e.
, outside the blood vessels), the inflammatory response is initially performed by retinal glial cells and the intraocular complement system, and overactivation of microglia and Müller cells releases cytokines and chemokines, further summoning the infiltration of circulating immune cells and inflammatory factors, accelerating the intraocular inflammatory response, and damaging the retina [13].


When damage to the blood-retinal barrier begins inside the blood vessels (such as in patients with diabetes mellitus or autoimmune uveitis), the failure of vascular endothelial function allows circulating immune cells and inflammatory factors to freely enter the retinal nervous layer, and the activation of the systemic immune system will greatly affect the immune response and visual function of the retina [14].


In addition, the disruption of the blood-retinal barrier makes it easier for environmental factors to enter the eye through the intestinal-blood-eye pathway and participate in the intraocular immune response [15
].

Fig.
2 Immune response and influencing factors in dry and wet retinal degeneration

(Source: Xu H et al.
, Prog Neurobiol, 2022)

III.
Summary and Outlook

In summary, the retina has a different
immune response than that of peripheral tissues due to its unique anatomical and immunological properties.

The authors of this paper for the first time propose to divide retinal degenerative lesions into dry and wet types according to whether the disease involves blood-retinal barrier damage and fluid extravasation, and systematically analyze the regulatory mechanism and characteristics of dry and wet retinal degeneration, pointing out that the dry type is mainly dominated by the retinal innate immune system, while the wet type is jointly involved
by the systemic immune system and the retinal inherent immune system.

In both cases, genetic, aging, and environmental factors are involved in the regulation of intraocular inflammatory responses, while in the wet form, due to the destruction of the blood-retinal barrier, intestinal microorganisms and circulating immune cells/factors are more likely to enter the eye and participate in retinal immune regulation
.

Although the classification of retinal degeneration depending on the state of the blood-retinal barrier can be complex in some cases, dry retinal degeneration can develop into wet type in the late stage, and a thorough understanding of the immunomodulation mechanisms of dry and wet retinal degeneration will help develop safe and effective treatments
.

 

Original link: https://doi.
org/10.
1016/j.
pneurobio.
2022.
102350

Professor Xu Heping

(Photo courtesy of: Xu Heping team, Aier Optometry Research Institute)

About the Author:

Professor Xu Heping is a tenured full professor at Queen's University Belfast in the United Kingdom and a professor at
the Aier Institute of Optometry.

Professor Xu is an internationally renowned ophthalmologist, whose research focuses on the activation and regulation of retinal inflammatory response and the mechanism of inflammation in age-related macular degeneration, diabetic retinopathy and uveitis, and seeks effective and safe treatments for these blinding eye diseases
.

For more information about Xu Lab, please visit https://pure.
qub.
ac.
uk/en/persons/heping-xu
.

In addition, Professor Xu's laboratory recruits associate researchers, postdoctoral fellows and research assistants from different disciplines, and the treatment is excellent, and young people with aspirations interested in visual science are welcome to join
.

Selected articles from previous issues [1] Mol Psychiatry—Niu Jianqin/Xiao Lan's team found that the variable shearing of oligodendroglial precursor cells DISC-Δ3 inhibits excitatory synaptic growth leading to schizophrenia [2] PNAS | Sun Bo's research group and collaborators found that time signals are the main factors regulating multicellular information networks[3] Cell Reports—Liu Sheng/Liu Yizhi's team mapped mammalian retinal ganglion cell multimodal maps[4] Cereb Cortex - default mode network in the treatment of electroshock in patients with depression [5] Mol Psychiatry - Xiong Wei's research group to analyze the neural circuit mechanism of fear enhancement of shock reflex [6] Transl Psychiatry—Early damage to cortical circuit plasticity and connectivity in mouse models of Alzheimer's disease[7] J Neurosci-Li Shao/Ma Tonghui's team revealed the orthogonal array structure of AQP4 in mouse with aquaporin point mutation and reduced its polar distribution at astrocyte endpodia [8] Cereb Cortex - Yu Yuguo team collaborated to construct a human brain energy and activity map to reveal the law of energy distribution [9] J Neurosci—Li Shao/Ma Tonghui team revealed the orthogonal array structure of AQP4 in aquaporin point mutation depolymerization mice and reduced its polarity distribution at the astrocyte endpodium [10] Cereb Cortex - Yu Yuguo team-built human brain energy and activity map to reveal energy distribution law High-quality scientific research training course recommendation [1] Seminar on Patch Clamp and Optogenetic and Calcium Imaging Technology (October 15-16, 2022 Tencent Conference) [2] R Language Clinical Prediction Biomedical Statistics Special Training (October 15-16, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing) Conference/Forum Preview & Review

[1] Trailer | Conference on Neuromodulation and Brain-Computer Interface (U.
S.
Pacific Time: October 12-13), Beijing Time[
2] Conference Report - The human brain and machine are gradually approaching, and the "black technology" of brain-computer interfaces shines into reality

Welcome to "Logical Neuroscience" [1] Talent Recruitment - "Logical Neuroscience" Recruitment Article Interpretation/Writing Position (Network Part-time, Online Office) References (Swipe Up and Down)

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