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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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“Forrester’s group suggest that in AMD, the balance between stress-induced damage and para-inflammation-related tissue repair and remodelling is disturbed.(39) It may be that the laser response changes the dynamics between protective repair mechanisms and the detrimental chronic inflammation in AMD as the result of som…”
BackgroundAssessment of Neutrophil/Lymphocyte Ratio in Patients with Age-related Macular Degeneration
İlhan, N., Dağlıoğlu, M. C., İlhan, Ö., Çoşkun, M., Tuzcu, E. A., Kahraman, H., & Keskın, U. (2014) · Ocular Immunology and Inflammation · doi:10.3109/09273948.2014.921715 · Cited by 89
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Santiago, A. R., Boia, R., Aires, I. D., Ambrósio, A. F., & Fernandes, R. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00820 · Cited by 89
“Moreover, AGEs upregulate RAGEs expression levels in pericytes via ROS production (Yamagishi, 2011).”
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“Although the majority of disease burden from vision loss derives from the advanced forms of AMD, it is known that drusen accumulation starts decades earlier and may promote a chronic state of parainflammation in the outer retina (Hageman et al., 2001; Lin et al., 2013; Xu et al., 2009).”
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“When para-inflammation develops into chronic and consistent inflammation, age-related retinal diseases, such as glaucoma and AMD, may occur.([17,22])”
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“Furthermore, Ccl3Abca4Rdh8 mice also displayed an increase of Ccl2 and Il1b, which are hallmarks of retinal inflammation after light (1).”
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“Professional immune cells, which reside in proximity to retinal blood vessels (perivascular macrophages) or within various layers of the neuropile (microglia), are of even more critical importance [40].”
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The role and therapeutic potential of melatonin in age‐related ocular diseases
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Zinc Nutrition and Inflammation in the Aging Retina
Gilbert, R. M., Pető, T., Lengyel, I., & Emri, E. (2019) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201801049 · Cited by 86
“In AMD, there is an increase in number of choroidal macrophages, which express complement receptor CRIg [259].”
BackgroundChanges in Retinal Glial Cells with Age and during Development of Age-Related Macular Degeneration
Telegina, D. V., Kozhevnikova, O. S., & Kolosova, N. G. (2018) · Biochemistry (Moscow) · doi:10.1134/s000629791809002x · Cited by 78
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Vagaja, N., Chinnery, H. R., Binz, N., Kezic, J. M., Rakoczy, E. P., & McMenamin, P. G. (2012) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.11-8601 · Cited by 73
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Garcia-Garcia, J., Usategui‐Martín, R., Sanabria, M. R., Fernandez-Perez, E., Orriols, J. J. T., & Coco, R. M. (2022) · Ophthalmic Research · doi:10.1159/000524942 · Cited by 77
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“AMD progression concurs with chronic and pathophysiological low-grade inflammation associated with a high cellular metabolism which contributes to generate ROS, oxidized lipoproteins, advanced glycation end-products, and apoptotic cells (Xu et al., 2009).”
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“Para-inflammation involves low levels of inflammatory activation, which can occur in the microglia and can contribute to damage of the retina if dysregulated (Figure 1) [31].”
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“In summary, in addition to inflammation that is clearly involved in AMD pathogenesis [8, 10, 11] we have seen that adaptive immunity is also probably at play in this disease.”
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Self-citationMechanisms of TNFα regulation in uveitis: Focus on RNA-binding proteins
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“The complexity of the underlying immunobiology should also remind us of the compelling but contrary evidence that altered immune responses (which increase with age) can also provide a capacity to maintain and preserve tissue function.(23) Evidence of NLRP3 activation and IL-18 upregulation in the RPE of human atrophic…”
BackgroundTLR2 Mediates the Innate Response of Retinal Muller Glia to Staphylococcus aureus
Shamsuddin, N., & Kumar, A. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100565 · Cited by 66
Mitochondrial DNA has a pro-inflammatory role in AMD
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“Along with astrocytic radial Müller glia, they rapidly re-activate following oxidative stress [4,12] and have been proposed to both preserve inner retinal tissue homeostasis, and generate a detrimental para-inflammatory response [13–16].”
BackgroundMeasurement of Subfoveal Choroidal Thickness Using Spectral Domain Optical Coherence Tomography
McCourt, E. A., Cadena, B. C., Barnett, C. J., Ciardella, A. P., Mandava, N., & Kahook, M. Y. (2010) · Ophthalmic surgery, lasers & imaging retina · doi:10.3928/15428877-20101031-14 · Cited by 64
Age-Related Macular Degeneration: Clinical Findings, Histopathology and Imaging Techniques
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Reactive retinal microglia, neuronal survival, and the formation of retinal folds and detachments
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“However, current consensus indicates that activated microglia and/or infiltrating macrophages contribute to the progression of age-related macular degeneration, glaucoma, and diabetic retinopathy (reviewed by Buschini et al., 2011; Karlstetter et al., 2010; Langmann, 2007; Xu et al., 2009).”
BackgroundFocus on molecular events in the anterior chamber leading to glaucoma
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“A large number of inflammatory genes, including genes involved in complement activation and inflammatory cytokine/ chemokine production, are upregulated, this in turn causing abnormal leukocyte–endothelial interactions and ultimately vascular damage [187].”
BackgroundJuel, H. B., Faber, C., Udsen, M. S., Folkersen, L., & Nissen, M. H. (2012) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.12-9963 · Cited by 62
Interleukin‐33 regulates tissue remodelling and inhibits angiogenesis in the eye
Theodoropoulou, S., Copland, D. A., Liu, J., Wu, J., Gardner, P. J., Ozaki, E., Doyle, S., Campbell, M. D., & Dick, A. D. (2016) · The Journal of Pathology · doi:10.1002/path.4816 · Cited by 62
“So, why patients convert from early or intermediate AMD (clinically manifest as drusen and RPE changes) to advanced AMD (including choroidal neovascularization) is purported to be as a switch from the ageing homeostatic regulatory response [5] to a pathological inflammatory response.”
BackgroundMechanism of Inflammation in Age-Related Macular Degeneration: An Up-to-Date on Genetic Landmarks
Parmeggiani, F., Sorrentino, F. S., Romano, M. R., Costagliola, C., Semeraro, F., Incorvaia, C., D’Angelo, S., Perri, P., Nadai, K. D., Roversi, E. B., et al. (2013) · Mediators of Inflammation · doi:10.1155/2013/435607 · Cited by 64
“At the retinal/choroidal interface, these AMD-related changes are particularly manifested by complement activation in RPEBM cells and microglia accumulation in subretinal space [47, 48, 71].”
BackgroundInfluentialProgress in developing rodent models of age-related macular degeneration (AMD)
Pandi, S. P. S., Ratnayaka, J. A., Lotery, A. J., & Teeling, J. L. (2020) · Experimental Eye Research · doi:10.1016/j.exer.2020.108404 · Cited by 63
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Self-citationTakahashi, Y., Chen, Q., Rajala, R. V. S., & Ma, J. (2015) · FEBS Letters · doi:10.1016/j.febslet.2015.03.010 · Cited by 61
Iannaccone, A., Giorgianni, F., New, D. D., Hollingsworth, T., Umfress, A. C., Alhatem, A., Neeli, I., Lenchik, N. I., Jennings, B., Calzada, J. I., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0145323 · Cited by 62
Immune Privilege: The Microbiome and Uveitis
Mölzer, C., Heissigerová, J., Wilson, H. M., Kuffová, L., & Forrester, J. V. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.608377 · Cited by 59
“Similar defects in the BRB are linked to agerelated disease in the eye which have an underlying inflammatory pathogenesis (74, 75).”
BackgroundSelf-citationA Review on Diabetic Retinopathy
Kour, V., Swain, J., Singh, J., Singh, H., & Kour, H. (2023) · Current Diabetes Reviews · doi:10.2174/0115733998253672231011161400 · Cited by 61
Differential Modulation of Retinal Degeneration by Ccl2 and Cx3cr1 Chemokine Signalling
Luhmann, U. F. O., Lange, C., Robbie, S. J., Munro, P., Cowing, J. A., Armer, H. E. J., Luong, V., Carvalho, L. S., MacLaren, R. E., Fitzke, F. W., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035551 · Cited by 62
T Cell-Mediated Autoimmunity in Glaucoma Neurodegeneration
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“For example, aging as a contributing factor of glaucoma is associated with the progressive loss of BRB integrity and a low level of retinal inflammation (69).”
BackgroundTwo-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice
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“Abca4−/−Rdh8−/− mice were used as an animal model that mimics fundamental changes in the retina relevant to human Stargardt disease and AMD.”
BackgroundInfluentialBeyond AREDS: Is There a Place for Antioxidant Therapy in the Prevention/Treatment of Eye Disease?
Kowluru, R. A., & Zhong, Q. P. W. (2011) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.10-6768 · Cited by 57
“Macrophages and leukocytes start to appear near drusen and neovascular membrane,(5,18) and macrophages not only produce reactive oxygen species (ROS) by phagocytosis, they also stimulate VEGF and secrete cytokines.(19) Increased VEGF further promotes neovascularization in the choroid, forming fragile new vessels, whic…”
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“However, this response is not stable and in aging persistent factors may promote a chronic dysregulation of para-inflammation, leading to pathology [26,28].”
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“Proinflammatory cytokines, such as TNF-α which is secreted by macrophages in the periphery and microglia in the ON and ONH, are involved in the process of glaucomatous neurodegeneration (Al-Gayyar et al., 2013; Xu et al., 2009).”
BackgroundRegulations of Retinal Inflammation: Focusing on Müller Glia
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Modulation of the Immune System for the Treatment of Glaucoma
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“Microglia are key players in neuroinflammation which is an immune response involving diverse mechanisms of different immune-related cells upon an insult as ischemia, infection, loss of tissue homeostasis, trauma or other events unpoising CNS homeostasis and also is a key process in glaucoma [114].”
BackgroundKeep an eye on adenosine: Its role in retinal inflammation
Santiago, A. R., Madeira, M. H., Boia, R., Aires, I. D., Rodrigues‐Neves, A. C., Santos, P. F., & Ambrósio, A. F. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107513 · Cited by 58
Complement regulation in the eye: implications for age-related macular degeneration
Wilke, G. A., & Apte, R. S. (2024) · Journal of Clinical Investigation · doi:10.1172/jci178296 · Cited by 55
“Aging in general is associated with the accumulation of oxidized lipids and proteins in the retina (67), as well as advanced glycation end products that interfere with RPE and BM function (68).”
Proapoptotic and survival signaling in the neuroretina at early stages of diabetic retinopathy.
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“Moreover, altered immune response regulation may shift the physiological equilibrium over a chronic-cumulative period, leading to a low-grade inflammatory degenerative process, known as para-inflammation, with the oxidative stress acting as a local trigger for retinal para-inflammatory responses.(23) Advances in biote…”
Wang, Y., Subramanian, P., Shen, D., Tuo, J., Becerra, S. P., & Chan, C. (2013) · ASN NEURO · doi:10.1042/an20130028 · Cited by 54
“Several evidence has linked it to intense parainflammation due to a wide range of causes, such as ageing, oxidative stress, genetic predisposition, and environmental elements (Xu et al., 2009; Rutar et al., 2011; Wang et al., 2011; Ambati and Fowler, 2012; Colak et al., 2012; Kauppinen et al., 2012; Tarallo et al., 20…”
BackgroundInfluentialTargeting neovascularization in ischemic retinopathy: recent advances
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The role of lymphocytes and phagocytes in age-related macular degeneration (AMD)
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Role of microglia/macrophage polarisation in intraocular diseases (Review)
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“Blood‑borne immune cells have a significant role in the microenvironment associated with RP and are consid‑ ered key mediators of the development of neurodegenerative diseases (98,99).”
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“, 2013), chronic inflammation becomes established (Catchpole et al., 2013; Hoh Kam et al., 2013; Xu et al., 2009), and retinal function declines (Kolesnikov et al.”
BackgroundCCL2-mediated inflammatory pathogenesis underlies high myopia-related anxiety
Zhu, X., Meng, J., Han, C., Wu, Q., Du, Y., Qi, J., Wei, L., Li, H., He, W., Zhang, K., et al. (2023) · Cell Discovery · doi:10.1038/s41421-023-00588-2 · Cited by 53
Oxidative stress and potential applications of free radical scavengers in glaucoma
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Recent advances in age-related meibomian gland dysfunction (ARMGD)
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Elevated protein carbonyl and HIF‐1α levels in eyes with proliferative diabetic retinopathy
Loukovaara, S., Koivunen, P., Inglés, M., Escobar, J., Vento, M., & Andersson, S. (2013) · Acta Ophthalmologica · doi:10.1111/aos.12186 · Cited by 51
“Different tissues have different microenvironmental constitutions and different amounts ⁄ types of free radicals may be generated (Xu et al. 2009).”
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“, inflammaging, para-inflammation) hypothesis of aging suggests that by-products of low-grade inflammatory processes may accumulate in tissues, and serve as a bridge between normal aging and age-related pathological processes (35, 36).”
Background
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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