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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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“state has been proposed to play an important role in other diseases, including type 2 diabetes, cardiovascular disease as well as in age-related retinal diseases (Medzhitov, 2008; Xu et al., 2009).”
BackgroundLoukovaara, S., Gucciardo, E., Repo, P. E., Vihinen, H., Lohi, J., Jokitalo, E., Salvén, P., & Lehti, K. (2015) · Acta Ophthalmologica · doi:10.1111/aos.12741 · Cited by 37
“Moreover, low-grade chronic inflammatory processes have been implicated in pathogenesis of DR (Medzhitov 2008; Xu et al. 2009).”
BackgroundYu, C. F., Yang, K., Meng, X., Cao, B., & Wang, F. (2020) · International Journal of Medical Sciences · doi:10.7150/ijms.38078 · Cited by 36
“Previous researches have shown that DR has different manifestations of abnormality, not only limited to microangiopathy [8,9].”
BackgroundKim, C., Park, S., Chun, Y., Song, W. J., Kim, H.-J., & Kim, J. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms160921008 · Cited by 36
“Reactive oxygen species or reactive nitrogen species are produced during normal physiological processes, but their production is accelerated under disease conditions and during the aging process [8].”
BackgroundResultInfluentialThe Role of Complement Dysregulation in Glaucoma
Hoppe, C., & Gregory-Ksander, M. S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25042307 · Cited by 35
“This low grade “para-inflammation” can also be observed in the aging retina with increased glial activation, breakdown of the blood-retinal barrier, upregulation of inflammatory genes involved in cytokine/chemokine production, and complement activation [56].”
BackgroundXie, J., Li, Y., Dai, J., He, Y., Sun, D., Dai, C., Xu, H., & Yin, Z. Q. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00341 · Cited by 35
“Studies have already shown that blood-derived immune cells are an important component of the disease-associated microenvironment, and they are considered to be critical mediators of neurodegenerative disease progression, not only in CNS but also in retina (Xu et al., 2009; Sevenich, 2018).”
BackgroundSelf-citationMaran, J. J., Adesina, M. M., Green, C. R., Kwakowsky, A., & Mugisho, O. O. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101954 · Cited by 38
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Self-citationRegulatory T cells limit age-associated retinal inflammation and neurodegeneration
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) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00724-w · Cited by 34
“Microglia are the localized immune cells in the retina, and they show an increased activation in the aged retina [1, 3].”
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Increased Levels of Inflammatory Immune Mediators in Vitreous From Pseudophakic Eyes
Jakobsson, G., Sundelin, K., Zetterberg, H., & Zetterberg, M. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.15-16837 · Cited by 34
Effect of long-term inflammation on viability and function of RPE cells
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“For instance, chronic low-grade inflammation or “para-inflammation”, associated with age-related accumulation of oxidised lipoproteins and free radicals, has been recently described as a potential reason for RPE and photoreceptor loss in the elderly and a contributing factor to AMD [70, 71].”
BackgroundBogdanov, P. M., Solà-Adell, C., Hernández, C., García‐Ramírez, M., Sampedro, J., Simó‐Servat, O., Valeri, M., Pasquali, C., & Simó, R. (2017) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2017.07.009 · Cited by 35
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“Parainflammation is an innate response of damaged tissues to induce tissue remodeling and maintain intraocular homeostasis.(151) The ECM in the TM normally responds by increasing or decreasing its permeability to adjust to physiologic IOP fluctuations, and proteins like metalloproteinases are involved in this recoilin…”
BackgroundCX3CL1/CX3CR1 and CCL2/CCR2 Chemokine/Chemokine Receptor Complex in Patients with AMD
Falk, M. K., Singh, A., Faber, C., Nissen, M. H., Hviid, T. V. F., & Sørensen, T. L. (2014) · PLoS ONE · doi:10.1371/journal.pone.0112473 · Cited by 34
“[1] Chemokine receptors such as CCR3 and CXCR3 have been associated with development of neovascular AMD while others such as CCR2 and CX3CR1 have been associated with drusen formation and development of early AMD.”
BackgroundInfluentialGeorge, A. K., Singh, M., Homme, R. P., Majumder, A., Sandhu, H. S., & Tyagi, S. C. (2018) · International Journal of Ophthalmology · doi:10.18240/ijo.2018.05.26 · Cited by 33
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“This stressful microenvironment elevates low-grade cellular activation and inflammation (parainflammation) which can be prolonged to sustain a DR disease-state.(4)”
BackgroundSelf-citationImmune Cells in Subretinal Wound Healing and Fibrosis
Szczepan, M., Llorián‐Salvador, M., Chen, M., & Xu, H. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.916719 · Cited by 34
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“However, chronic para-inflammation can lead to disease progression and is thought to be an important process in age-related retinal diseases [38].”
Enhanced Ccl2-Ccr2 signaling drives more severe choroidal neovascularization with aging
Robbie, S. J., Georgiadis, A., Barker, S. E., Durán, Y., Smith, A. J., Ali, R. R., Luhmann, U. F. O., & Bainbridge, J. W. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.12.019 · Cited by 32
“, 2012) and upregulation of the innate immune system is particularly prominent (Anderson et al., 2010; Luhmann and Ali, 2012; Xu et al., 2009).”
M’Barek, K. B., & Monville, C. (2019) · Stem Cells International · doi:10.1155/2019/4568979 · Cited by 38
“Environmental causes include hypertension, obesity, diet, sunlight exposure, chronic inflammation, and smoking [12, 13].”
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Gemenetzi, M. K., & Lotery, A. J. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03421-w · Cited by 32
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“Therefore, although para-inflammation is initially activated in response to OS to maintain rescue photoreceptors, stress-induced chronic inflammatory is the main factor responsible for photoreceptor degeneration [16,19].”
BackgroundImmune response in retinal degenerative diseases – Time to rethink?
Xu, H., & Chen, M. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102350 · Cited by 33
“For example, in response to age-related oxidative damage, microglia and the complement system are activated at low levels in the retina (Chen et al., 2019; Xu et al., 2009).”
BackgroundSelf-citationKyger, M., Worley, A. H., & Adamus, G. (2012) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2012.10.007 · Cited by 32
“Waste products that accumulate in the retina, including drusen-containing complement factors, immunoglobulins, and pro-inflammatory cytokines/chemokines cause progressive loss of vision (Penfold et al., 2001; Ding et al., 2009; Xu et al., 2009).”
BackgroundA Brief Review on the Pathological Role of Decreased Blood Flow Affected in Retinitis Pigmentosa
Yang, Y., Peng, J., Ying, D., & Peng, Q. (2018) · Journal of Ophthalmology · doi:10.1155/2018/3249064 · Cited by 33
“However, cones can also undergo apoptosis following the loss of rods, due to the activation of apoptotic death in intracellular signaling and mediators in photoreceptors [13].”
Bruch’s Membrane and the Choroid in Age-Related Macular Degeneration
Edwards, M., & Lutty, G. A. (2021) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-030-66014-7_4 · Cited by 32
Brandli, A. A., Vessey, K. A., & Fletcher, E. L. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03055-1 · Cited by 33
“Drusen also contain mediators of inflammation (e.g. C-reactive protein) including many complement related proteins (e.g. C3a and C5a) suggesting chronic activation of the innate immune system in the development of early stage disease [12, 13].”
BackgroundSzabadfi, K., Reglődi, D., Szabo, A., Szalontai, B., Kovács-Valasek, A., Sétáló, G., Kiss, P., Tamás, A., Wilhelm, M., & Gabriel, R. (2016) · Neurotoxicity Research · doi:10.1007/s12640-015-9593-1 · Cited by 31
“Examination of the RPE is of primary importance since this is a selective exchange platform and an immuneprivileged site (Xu et al. 2009).”
Natoli, R., Fernando, N., Dahlenburg, T., Jiao, H., Aggio‐Bruce, R., Barnett, N. L., de la Barca, J. M. C., Tcherkez, G. G. B., Reynier, P., Fang, J., et al. (2018) · PubMed Central · Cited by 31
Metruccio, M. M. E., Wan, S. J., Horneman, H. F., Kroken, A. R., Sullivan, A. B., Truong, T. N., Mun, J. J., Tam, C. K. P., Frith, R., Welsh, L., et al. (2018) · The Ocular Surface · doi:10.1016/j.jtos.2018.11.006 · Cited by 32
“While not previously described in the cornea, para-inflammation is known to occur in the aging retina and it relates to the pathogenesis of some retinal diseases [63,64].”
BackgroundYuan, Z., Chen, X., Yang, W., Lou, B., Ye, N., & Liu, Y. (2019) · PubMed Central · Cited by 31
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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