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Para-inflammation in the aging retina
Abstract
Para-inflammation is a tissue adaptive response to noxious stress or malfunction and has characteristics that are intermediate between basal and inflammatory states (Medzhitov, 2008). The physiological purpose of para-inflammation is to restore tissue functionality and homeostasis. Para-inflammation may become chronic or turn into inflammation if tissue stress or malfunction persists for a sustained period. Chronic para-inflammation contributes to the initiation and progression of many human diseases including obesity, type 2 diabetes, atherosclerosis, and age-related neurodegenerative diseases. Evidence from our studies and the studies of some others suggests that para-inflammation also exists in the aging retina in physiological conditions and might contribute to age-related retinal pathologies. The purpose of this review is to introduce the notion of "para-inflammation" as a state between frank, overt destructive inflammation and the non-inflammatory removal of dead or dying cells by apoptosis, to the retinal community. In diabetes and atherosclerosis, leukocytes particularly monocytes and vascular endothelial cells are constantly under noxious stress due to glycaemic and/or lipidaemic dysregulation. These blood-borne stresses trigger para-inflammatory responses in leukocytes and endothelial cells by up-regulating the expression of adhesion molecules or releasing cytokines/chemokines, which in turn cause abnormal leukocyte-endothelial interactions and ultimately vascular damage. In the aging retina, on the other hand, oxidized lipoproteins and free radicals are considered to be major causes of tissue stress and serve as local triggers for retinal para-inflammation. Microarray analysis has revealed the up-regulation of a large number of inflammatory genes, including genes involved in complement activation and inflammatory cytokine/chemokine production, in the aging retina. Para-inflammatory responses in the neuroretina of aged mice are characterized by microglial activation and subretinal migration, and breakdown of blood-retinal barrier. At the retinal/choroidal interface para-inflammation is manifested by complement activation in Bruch's membrane and RPE cells, and microglia accumulation in subretinal space. With age, para-inflammatory changes have also been observed in the choroidal tissue, evidenced by 1) increased thickness of choroid; 2) increased number of CD45(+)CRIg(+) macrophages; 3) morphological abnormalities in choroidal melanocytes; and 4) fibrosis in choroidal tissue. An increased knowledge of contribution of retinal para-inflammation to various pathological conditions is essential for the better understanding of the pathogenesis of various age-related retinal diseases including diabetic retinopathy, glaucoma and age-related macular degeneration.
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“While the immune tolerance mechanism tries to counterbalance inflammation, danger signals in the retina may still result in mild activation of the innate immune system, in a process recently termed para-inflammation [27][28][29].”
From Risk mitigation of immunogenicity: a key to personalized retinal gene therapy (2021) · cites this paper as [28]
In the citing paper
“In AMD, the oxidative stress may elicit a response also known as “para-inflammation” where the innate immune system induces a mild inflammatory response to restore homeostasis that, if chronic, may contribute to AMD through imbalanced inflammatory response [28].”
From Risk mitigation of immunogenicity: a key to personalized retinal gene therapy (2021) · cites this paper as [28]
In the citing paper
“Retinal inflammation and degeneration have been reported to commence earlier than 24 months in rodents”
From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [129]
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Zapata, G. (2011) · Oxidative stress in applied basic research and clinical practice · doi:10.1007/978-1-61779-071-3_8 · Cited by 2
“Different studies have demonstrated and associated the degenerative processes of the retina with an oxidative imbalance both in elder people and animal models [ 93 ].”
BackgroundNew Frontiers of Retinal Therapeutic Innovation & Strategic Insights
Qiu, T. G., & Laties, A. M. (2015) · Cited by 2
Çetin, E. N., Kutlu, S. S., Parça, O., Kutlu, M., & Pekel, G. (2018) · Eye & Contact Lens Science & Clinical Practice · doi:10.1097/icl.0000000000000468 · Cited by 2
Inflammatory Response and Mediators in Retinal Injury
Chan, C., & Smith, W. M. (2012) · Elsevier eBooks · doi:10.1016/b978-1-4557-0737-9.00025-4 · Cited by 2
Investigation of Blood Characteristics in Nonsyndromic Retinitis Pigmentosa: A Retrospective Study
Yang, Y., Deng, Y., Tian, Y., Yao, Z., Zhou, Y.-S., Wang, Y., Peng, Q., & Peng, J. (2019) · Journal of Ophthalmology · doi:10.1155/2019/1902915 · Cited by 2
“-e mechanisms leading to cell death are expected to disrupt material movement and energy utilization, cause cell vulnerability, stimulate local hypoperfusion, hypoxia, and vascular endothelial cells injury, and further affect blood flow [12, 13].”
BackgroundRecent Advances and New Perspectives in Managing Macular Degeneration
Davey, P. G. (2021) · IntechOpen eBooks · doi:10.5772/intechopen.91530 · Cited by 2
Efficacy of intravitreal dexamethasone implant in chronic central serous chorioretinopathy
Behera, U. C., Shah, M. S., Kelgaonkar, A., Sahoo, J., Narayanan, R., & Sadda, S. (2023) · Indian Journal of Ophthalmology - Case Reports · doi:10.4103/ijo.ijo_2523_22 · Cited by 2
Inflammation in Age-Related Macular Degeneration – Implications for Therapy
Chen, M., & Xu, H. (2012) · InTech eBooks · doi:10.5772/25658 · Cited by 2
“Oxidative stress and para-inflammation in the aging retina (Xu et al. 2009).”
BackgroundInfluentialSelf-citationAge-Related RPE changes in Wildtype C57BL/6J Mice between 2 and 32 MonthsPreprint
Shelton, D. A., Gefke, I., Summers, V. R., Kim, Y., Yu, H., Getz, Y., Ferdous, S., Donaldson, K. J., Liao, K., Papania, J. T., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.30.574142 · Cited by 2
“…needed to better understand the dynamics of their function and how expression of specific markers may elicit a pro-or anti-inflammatory program in the subretinal space [(83),(90) Multiple groups have detailed how deterioration in visual function manifests with increased age in mice [ (91–93)(94)].”
BackgroundNeelamegam, M., Nawi, N., Bashah, N. S. A., Yap, S. H., Zulhaimi, N. S., Kamarulzaman, A., Kamaruzzaman, S. B., Ramli, N. M., & Rajasuriar, R. (2023) · Frontiers in Ophthalmology · doi:10.3389/fopht.2023.1251126 · Cited by 1
GÖZ ALMASI TOXUMALARINDA HİPOKSİYA İLƏ İNDUKSİYA OLUNMUŞ APOPTOZ
Galbinur, P. I. M., Маркитантова, Ю. В., Babaev, K., Алексеевна, Р. А., & Akberova, S. I. (2022) · Azerbajdžanskij medicinskij žurnal · doi:10.34921/amj.2022.4.022 · Cited by 1
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Retinal Amyloid Clearance Enhanced by 40-Hz Light Flicker via MHC-II + Microglia Regulation in Mice
Sheng, W., Wang, Q., Huang, Y., Gu, J., Ding, C., Cui, Z., Tang, S., Xia, X., & Chen, J. (2026) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.67.1.32 · Cited by 1
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“Previously categorized as M1 (pro-inflammatory) or M2 (anti-inflammatory), microglia are now recognized to exist along a continuum, modulated by local cues and inhibitory neuron–microglia pathways, such as CD200-CD200R and CX3CL1-C–X3–”
Myeloid Cell Protein Tyrosine Phosphatase 1B Drives Retinal Neurodegeneration in Diabetic Mice
Ali, A., Boyne, M., Othman, A., Kamli-Salino, S., Kuffová, L., Forrester, J. V., & Delibegović, M. (2026) · Diabetes · doi:10.2337/db25-0904 · Cited by 1
Self-citationThe Role of Retinal Oxidative and Nitrative Injury in Glaucomatous Neurodegeneration
Doğan, S., & Asl, M. (2011) · InTech eBooks · doi:10.5772/18513 · Cited by 1
“Oxidized proteins, lipids, and DNA become para-inflammatory stimuli and signal to resident immune cells, mainly including microglia, to initiate an innate immune response (Xu et al., 2009).”
BackgroundEnhancing Inflammation as an Adjuvant to Neovascular AMD Therapy
Dick, A. D. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.15-17613 · Cited by 1
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The possible Role of IFN-γ & TNF-α in bacterial eye infection patients
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Examination of the Neuroprotective Effects of URB597 in Young and Aged Rat Retina
Slusar, J. E. (2010) · Library and Archives Canada (Government of Canada) · Cited by 1
Autophagy in Ocular Pathophysiology
Mitter, S. K., & Boulton, M. E. (2016) · InTech eBooks · doi:10.5772/64667 · Cited by 1
“Para-inflammation is required for retinal tissue homeostasis plays a crucial role in tissue repair/remodeling, but when para-inflammation becomes chronic or progresses to destructive inflammation, retinal damage and pathology may ensue (reviewed in [134]).”
BackgroundDie alternde Retina im Kontext zerebraler neurodegenerativer Erkrankungen
Böhm, M. R. R., & Thanos, S. (2017) · Klinische Monatsblätter für Augenheilkunde · doi:10.1055/s-0043-105266 · Cited by 1
“Adaptive Prozesse innerhalb der Retina haben im Sinne der Parainflammation das Ziel, eine Gewebsreparatur aus den chronischen Schädigungen zu erreichen [43].”
BackgroundEffects of Dietary Omega-3 Fatty Acid Consumption
Zanwar, A. A., Joshi, A., & Hegde, M. V. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-811959-4.00025-0 · Cited by 2
The involvement of NK1 and Y2 receptor in the development of laser-induced CNVs in C57Bl/6N mice
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Normal gözlerde yaş ve cinsiyetin retina kalınlığına etkisi’
Ongun, G. T. (2018) · Pamukkale Medical Journal · doi:10.31362/patd.428103 · Cited by 1
Dunn, J. P. (2022) · Springer eBooks · doi:10.1007/978-3-030-42634-7_32 · Cited by 1
Loss of Pigment Epithelium Derived Factor Sensitizes C57BL/6J Mice to Light-Induced Retinal DamagePreprint
Shelton, D. A., Papania, J. T., Getz, T. E., Sellers, J. T., Giradot, P. E., Chrenek, M. A., Grossniklaus, H. E., Boatright, J. H., & Nickerson, J. M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.04.626802 · Cited by 1
Nowak, J. Z. (2014) · Oxidative stress in applied basic research and clinical practice · doi:10.1007/978-1-4939-0440-2_24
Alterung der Netzhaut und des retinalen Pigmentepithels
Boulton, M. (2011) · Springer eBooks · doi:10.1007/978-3-642-20870-6_3
Editorial Inflammation in Retinal Disease
Whitcup, S. M., Nussenblatt, R. B., Lightman, S., & Hollander, D. (2013)
Asymmetric dimethylarginine and homocysteine in exudative age-related macular degeneration
Javadzadeh, A., Ghorbanihaghjo, A., Mansouri, S., & Rashtchizadeh, N. (2015) · Journal of Analytical Research in Clinical Medicine · doi:10.15171/jarcm.2015.037
Metadata
- Authors
- Xu, H., Chen, M., & Forrester, J. V.
- Affiliations
- University of Aberdeen (GB)
- Corresponding author
- Xu, Heping
- Venue
- Progress in Retinal and Eye Research
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 28
- Issue
- 5
- Pages
- 348-368
- ISSN
- 1350-9462 (ISSN-L)
- OpenAlex
- W2034060753
- Cited by
- 659
- References
- 276
- Citations by year
- 2026: 23 · 2025: 22 · 2024: 44 · 2023: 41 · 2022: 39 · 2021: 54 · 2020: 43 · 2019: 30 · 2018: 44 · 2017: 45 · 2016: 38 · 2015: 56 · 2014: 42 · 2013: 42 · 2012: 42
- FWCI
- 6.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Progress in Retinal and Eye Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- microglial activation, complement activation, blood-retinal barrier breakdown, choroid, retinal pigment epithelium, Bruch's membrane, oxidative stress, oxidized lipoproteins, diabetic retinopathy, glaucoma, choroidal neovascularization
- MeSH terms
- Aging, Animals, Blood-Retinal Barrier, Diabetic Retinopathy, Glaucoma, Humans, Inflammation, Macular Degeneration, Retina, Retinitis, Up-Regulation, Oxidative Stress
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