The DOI matches its Crossref record; 275 of the 276 references it cites were found in a registry or an index.
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]
Citations
Cites
Aging: a theory based on free radical and radiation chemistry
Harman, D. (1956) · Journal of Gerontology · doi:10.1093/geronj/11.3.298 · Cited by 8,567
The number of people with glaucoma worldwide in 2010 and 2020
Quigley, H. A. (2006) · British Journal of Ophthalmology · doi:10.1136/bjo.2005.081224 · Cited by 7,417
Origin and physiological roles of inflammation
Medzhitov, R. (2008) · Nature · doi:10.1038/nature07201 · Cited by 6,618
Alternative activation of macrophages
Gordon, S. (2003) · Nature Reviews Immunology · doi:10.1038/nri978 · Cited by 6,189
A human homologue of the Drosophila Toll protein signals activation of adaptive immunity
Medzhitov, R., Preston-Hurlburt, P., & Janeway, C. A. J. (1997) · Nature · doi:10.1038/41131 · Cited by 6,137
Complement factor H polymorphism in age-related macular degeneration
Klein, R. J., Zeiss, C., Chew, E. Y., Tsai, J.-Y., Sackler, R. S., Haynes, C., Henning, A. K., SanGiovanni, J. P., Mane, S. M., Mayne, S. T., et al. (2005) · Science · doi:10.1126/science.1109557 · Cited by 4,492
Fadok, V. A., Bratton, D. L., Konowal, A., Freed, P. W., Westcott, J. Y., & Henson, P. M. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1112 · Cited by 3,166 · cited 1×
“Uptake of apoptotic cells by phagocytes induces anti-inflammatory responses, including the production of transforming growth factor b (TGF-b) and interleukin-10 production (Fadok et al., 1998a,b; Voll et al., 1997).”
BackgroundBiology of disease: free radicals and tissue injury.
Freeman, B. Α., & Jd, C. (1982) · PubMed · Cited by 3,038
Prevalence of Age-Related Macular Degeneration in the United States
The Eye Diseases Prevalence Research Group* (2004) · Archives of Ophthalmology · doi:10.1001/archopht.122.4.564 · Cited by 2,774
Signaling to NF-κB by Toll-like receptors
Kawai, T., & Akira, S. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.09.002 · Cited by 2,468
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Practitioner, G. (2015)
Kimura, K. (2015) · Yamaguchi Medical Journal · doi:10.2342/ymj.64.11
Anti-angiogenesis Therapy in Diabetic Retinopathy
Stewart, M. W. (2017) · Springer eBooks · doi:10.1007/978-3-319-61115-0_13
Rath, P. C. (2017) · Healthy ageing and longevity · doi:10.1007/978-3-319-63001-4_13 · Cited by 1
Distinct Oral Neutrophil Subsets Define Health and Disease States
Hassanpour, S. (2017) · TSpace (University of Toronto)
Depot Indocyanine Green Dye for in vivo visualization of infiltrating leukocytes
Sim, D. A., Chu, C. J., Powner, M. B., Selvam, S., Tufail, A., Egan, C. A., Bainbridge, J. W., Lee, R., Dick, A. D., & Fruttiger, M. (2015) · UCL Discovery (University College London)
Lamin, A. (2019) · UCL Discovery (University College London)
Suprachoroidale minimalinvasive Glaukomchirurgie: Verfahren und klinische Ergebnisse
Erb, C. (2018) · Der Ophthalmologe
Assessment of neutrophil-lymphocyte ratios in patients with dry age-related macular degenerationPreprint
Sannan, N., Ramadhan, M., Elsayid, M. A., Ghamdi, H. K. A. A., ALGHAMDI, L., & Alqahtani, M. B. (2021) · Research Square · doi:10.21203/rs.3.rs-965139/v1
(2021) · Elsevier eBooks · doi:10.1016/b978-0-323-90467-4.00011-5
Bringmann, A., & Wiedemann, P. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-90467-4.00003-6
Mulki, L., Sweigard, J. H., & Connor, K. M. (2014) · Journal of Visualized Experiments · doi:10.3791/52130-v
Calcagni, A., Howells, O., Bartlett, H. E., Denniston, A. K., Gibson, J. M., Hogg, C. R., Matthews, T. D., & Eperjesi, F. (2022) · Eye · doi:10.1038/s41433-021-01875-6
Assessment of Neutrophil-Lymphocyte Ratios in Patients with Dry Age-related Macular DegenerationPreprint
Sannan, N., RAMADHAN, M., Elsayid, M., Alghamdi, H. A., ALGHAMDI, L., & AlQahtani, M. M. (2021) · Research Square · doi:10.21203/rs.3.rs-965139/v2
Patro, N., Kushwaha, S. S., & Patro, I. K. (2022) · Springer eBooks · doi:10.1007/978-981-16-8313-8_20
Jager, M. J., & Bronkhorst, I. H. G. (2019) · Springer eBooks · doi:10.1007/978-3-030-04489-3_6
Dunn, J. P. (2020) · Springer eBooks · doi:10.1007/978-3-319-90495-5_32-1
Benefits of genetic and immunohistochemical markers in understanding abnormalities in aging retina
Ormenişan, D.-M., & Borda, A. (2022) · Romanian Journal of Morphology and Embryology · doi:10.47162/rjme.63.1.12
Introductory Chapter: Advances in Management of AMD
Davey, P. G. (2022) · IntechOpen eBooks · doi:10.5772/intechopen.105436
Inflammasomes in the pathobiology of degenerative retinopathies
Silke, E., Cahill, M. T., Campbell, M., & Doyle, S. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-91802-2.00021-9 · Cited by 1
A holistic approach to eye care part 2: Age-related macular degeneration; an inflammatory disease
Narayan, R. (2020) · Optician · doi:10.12968/opti.2020.10.8335
Regulatory T cells limit age-associated retinal inflammation and neurodegenerationPreprint
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Ephrin B1 Regulates Inflammatory Pathways in Retinal Müller Cells
Liu, L.-Z., Jiang, Y., Al‐Shabrawey, M., & Steinle, J. J. (2024) · Journal of Diabetes and Clinical Research · doi:10.33696/diabetes.6.056
“For the last several decades, the role of inflammation has been appreciated in the retina [1,2].”
BackgroundJager, M. J., Ma, S., Pinos, E. D. L., & Bronkhorst, I. H. G. (2025) · Springer eBooks · doi:10.1007/978-3-031-75907-9_7
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Prokopiou, E., & Georgiou, T. (2025) · Springer eBooks · doi:10.1007/978-3-031-84200-9_16
Sasaki, M., Cheong, K. X., Chong, C. C. Y., Yu, M., Hanyuda, A., Yuki, K., Negishi, K., Hashimoto, S., Fujiwara, K., Sonoda, K., et al. (2025) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.66.6.36
“6,7 .”
Items of Examination of Intraocular Fluid
Tao, Y. K., & Hwang, D. (2025) · Springer eBooks · doi:10.1007/978-981-96-2486-7_4
Du, X., Peñalva, R. G., Little, K., Kissenpfennig, A., Chen, M., & Xu, H. (2021) · Figshare · doi:10.6084/m9.figshare.14059735
Self-citationDu, X., Peñalva, R. G., Little, K., Kissenpfennig, A., Chen, M., & Xu, H. (2021) · Figshare · doi:10.6084/m9.figshare.14059744
Self-citationDu, X., Peñalva, R. G., Little, K., Kissenpfennig, A., Chen, M., & Xu, H. (2021) · Figshare · doi:10.6084/m9.figshare.14059741
Self-citationDu, X., Peñalva, R. G., Little, K., Kissenpfennig, A., Chen, M., & Xu, H. (2021) · Figshare · doi:10.6084/m9.figshare.14059747
Self-citationBiber, J., Jabri, Y., Glänzer, S., Dort, A., Hoffelner, P., Schmidt, C. Q., Bludau, O., Pauly, D., & Grosche, A. (2024) · Figshare · doi:10.6084/m9.figshare.26684625
Llorián‐Salvador, M., de la Fuente, A. G., McMurran, C. E., Dashwood, A., Dooley, J., Liston, A., Peñalva, R. G., Dombrowski, Y., Stitt, A. W., & Fitzgerald, D. C. (2024) · Figshare · doi:10.6084/m9.figshare.25556648
Du, X., Peñalva, R. G., Little, K., Kissenpfennig, A., Chen, M., & Xu, H. (2021) · Figshare · doi:10.6084/m9.figshare.14059738
Self-citationLlorián‐Salvador, M., de la Fuente, A. G., McMurran, C. E., Dashwood, A., Dooley, J., Liston, A., Peñalva, R. G., Dombrowski, Y., Stitt, A. W., & Fitzgerald, D. C. (2024) · Figshare · doi:10.6084/m9.figshare.25556534
Dabouz, R., Cheng, C. W. H., Abram, P., Omri, S., Cagnone, G., Sawmy, K. V., Joyal, J., Desjarlais, M., Olson, D. M., Weil, A. G., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13297102
Karg, M. M., Moorefield, M., Hoffmann, E., Philipose, H., Krasniqi, D., Hoppe, C., Shu, D. Y., Shirahama, S., Ksander, B. R., & Saint‐Geniez, M. (2023) · Figshare · doi:10.6084/m9.figshare.24311671
Yi, C., Liu, J., Deng, W., Luo, C., Qi, J., Chen, M., & Xu, H. (2023) · Figshare · doi:10.6084/m9.figshare.22604159
Self-citationLlorián‐Salvador, M., de la Fuente, A. G., McMurran, C. E., Dashwood, A., Dooley, J., Liston, A., Peñalva, R. G., Dombrowski, Y., Stitt, A. W., & Fitzgerald, D. C. (2024) · Figshare · doi:10.6084/m9.figshare.26702587
Du, X., Peñalva, R. G., Little, K., Kissenpfennig, A., Chen, M., & Xu, H. (2021) · Figshare · doi:10.6084/m9.figshare.14059750
Self-citationCiftci, I. H., Özkan, A. D., Erman, G., Kılbaş, İ., & Aydemir, Ö. (2025) · Biomedicines · doi:10.3390/biomedicines14010050
“They reported that ARPE-19 cells increased inflammatory cytokine production when exposed to various irritants, and IL-1 β release was particularly significantly elevated [29].”
Yang, H., Liu, B., Zhang, Y., Zhang, Z., Tan, H., & Li, X. (2026) · International Journal of Retina and Vitreous · doi:10.1186/s40942-026-00813-6
“Such coordinated regulation may reduce the infiltration of senescent T cells into retinal tissue and contribute to improved immune micro-environment homeostasis [7, 84].”
Bai, J., Wu, Z., Wan, Z., Zhao, C., Liu, Y., & Wang, T. (2026) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2026.101457
Wang, T., Huang, W., Li, Z., Cao, Z., Pu, K., shao, D., Wu, J., Li, J., & Zhao, N. (2026) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5c00870
Charles‐Messance, H. (2018) · theses.fr (ABES) · doi:10.70675/674377b7z4bf8z451cz9328zbe6648512747
Rôle du facteur H du complément et du récepteur CD47 dans l’inflammation sous-rétinienne
Augustin, S. (2021) · theses.fr (ABES) · doi:10.70675/be8ffdbez2125z4378za1bbzb8ba72c35267
Armendariz, B. G., & Kent, D. (2026) · Molecular vision · doi:10.63500/mv_v32_22
The immune system as a regulator of normal physiology
Forrester, J. V., Kuffová, L., & Dick, A. D. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1867359
Self-citationZiafati, M., Valizadeh, Z., Rahimi, S., Valizadeh, A., Abbasian, L., & Arévalo, J. F. (2026) · Survey of Ophthalmology · doi:10.1016/j.survophthal.2026.07.012
Toro, M. D., Avitabile, A., Amato, R., Rusciano, D., & Gagliano, C. (2026) · Antioxidants · doi:10.3390/antiox15081034 · Cited by 1
“Mitochondrial injury, impaired lysosomal degradation, lipofuscin accumulation, oxidative modification of lipids and proteins, and chronic para-inflammatory signaling begin to reinforce one another [3,16].”
Esser, E., Kuhrt, H., Ziemssen, F., & Hollborn, M. (2026) · Molecular vision · doi:10.63500/mv_v32_210
“PCR results are shown as x-fold change to untreated control (1).”
Pilotto, E., Parolini, F., Edwards, M. M., Midena, E., & Midena, G. (2026) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.67.10.56
“44 Macrophages may play a key role in AMD pathogenesis contributing to Bruch’s membrane disruption.”
Exploring the role of infectious pathogens in Alzheimer’s disease neuroinflammation
Vaiasicca, S., Mangiaterra, G., Citterio, B., Piccioni, G., Orlando, F., Giorgetti, B., Cianfruglia, L., Giacconi, R., Fumarola, S., Cardelli, M., et al. (2026) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2026.1919289
Yue, H., Lu, J., Yasha, Z., Xiao, L., Deng, Y., Peng, Q., & Yang, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1958864
Wang, X., Bi, Y., Liu, Y., Nie, Y., Ding, J., Yu, L., & Mao, S. (2026) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.67.12.30
Pizzirani, S. (2026) · Veterinary Ophthalmology · doi:10.1111/vop.70283
The Role of Oxidative Stress in the Retinal Lesion of Ccl2/Cx3cr1 Deficiency Mouse on rd8 Background
Tuo, J. (2012) · Humana Press eBooks · doi:10.1007/978-1-61779-606-7_17
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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