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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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“Within tissues, the intermediary immune state that allows the host to adequately respond to low-grade noxious agents or tissue damage, without clinical signs of inflammation, has been termed parainflammation (Medzhitov 2008; Xu et al. 2009; Chovatiya and Medzhitov 2014).”
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Targeting the complement system for the management of retinal inflammatory and degenerative diseases
Xu, H., & Chen, M. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.03.001 · Cited by 168
“The retina contains at least three types of innate immune cells: microglia, perivascular macrophages, and dendritic cells (DCs) (Forrester et al., 2010; Xu et al., 2009).”
BackgroundSelf-citationNLRP3 inflammasome activation is associated with proliferative diabetic retinopathy
Loukovaara, S., Piippo, N., Kinnunen, K., Hytti, M., Kaarniranta, K., & Kauppinen, A. (2017) · Acta Ophthalmologica · doi:10.1111/aos.13427 · Cited by 160
Good News–Bad News: The Yin and Yang of Immune Privilege in the Eye
Forrester, J. V., & Xu, H. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00338 · Cited by 153
Self-citationCataract Surgery Induces Retinal Pro-inflammatory Gene Expression and Protein Secretion
Xu, H., Chen, M., Forrester, J. V., & Lois, N. (2010) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.10-6001 · Cited by 154
“We have shown previously that RPE cells can produce CFB.20,21 Further studies have shown that the production CFB by RPE cells can be upregulated by inflammatory cytokines TNF- and IFN- ,20,21 and IL-1 .37 A more recent study has shown that a variety of complement components can be produced locally in the eye by the ne…”
BackgroundSelf-citationThe immune response in glaucoma: A perspective on the roles of oxidative stress
Tezel, G. (2010) · Experimental Eye Research · doi:10.1016/j.exer.2010.07.009 · Cited by 145
“Oxidative stress and accumulation of oxidation products are considered to be major factors serving as local triggers for retinal para-inflammatory responses with aging and have been associated with the pathogenesis of aging-related retinal diseases (Xu et al., 2009).”
InfluentialNowak, J. Z. (2013) · Pharmacological Reports · doi:10.1016/s1734-1140(13)71005-3 · Cited by 145
Diabetic retinopathy and dysregulated innate immunity
Xu, H., & Chen, M. (2017) · Vision Research · doi:10.1016/j.visres.2017.04.013 · Cited by 144
“Nevertheless, microglial activation is mild at the early stages of DR, and the low-levels of resident innate immune cell activation (para-inflammation) under chronic stress conditions is regarded as a protective response to maintain homeostasis (Chen & Xu, 2015; Medzhitov, 2008; Xu et al., 2009).”
BackgroundSelf-citationNeuroinflammation as Fuel for Axonal Regeneration in the Injured Vertebrate Central Nervous System
Bollaerts, I., houcke, J. V., Andries, L., Groef, L. D., & Moons, L. (2017) · Mediators of Inflammation · doi:10.1155/2017/9478542 · Cited by 138
“This includes a slight but significant increase in microglial cell density, which is also observed in some other brain regions [141, 142], but not in all [143, 144].”
BackgroundMechanism of Inflammation in Age-Related Macular Degeneration
Parmeggiani, F., Romano, M., Costagliola, C., Semeraro, F., Incorvaia, C., D’Angelo, S., Perri, P., Palma, P. D., Nadai, K. D., & Sebastiani, A. (2012) · Mediators of Inflammation · doi:10.1155/2012/546786 · Cited by 140
“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].”
BackgroundInfluentialMicroglia-Müller Cell Interactions in the Retina
Wang, M., & Wong, W. T. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-3209-8_42 · Cited by 136
“As microglial and Müller cells responses to disease and injury have been ascribed both adaptive and maladaptive aspects, it is of interest to determine if and how microglia- Müller cell interactions help shape the features of the overall retinal injury response [6, 7, 12].”
BackgroundInflammaging in Skin and Other Tissues - The Roles of Complement System and Macrophage
Zhuang, Y., & Lyga, J. W. (2014) · Inflammation & Allergy - Drug Targets · doi:10.2174/1871528113666140522112003 · Cited by 138
“As with aged macrophages in retina, the microglia show diminished function upon aging, evidenced by reduced size of dendritic arbors, slow to migrate to site of tissue stress and slow to leave the site afterwards [19].”
BackgroundInfluentialImmune Activation in Retinal Aging: A Gene Expression Study
Chen, M., Muckersie, E., Forrester, J. V., & Xu, H. (2010) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.09-5103 · Cited by 130
“The host immune system provides this scavenging and repair role, thus restoring tissue functionality, and this process has been described as a form of physiological inflammation (para-inflammation).(6,7) However, the system is not foolproof and with increasing age, an imbalance in tissue homeostasis may occur either a…”
BackgroundSelf-citationThe role of glia in retinal vascular disease
Coorey, N. J., Shen, W., Chung, S. H., Zhu, L., & Gillies, M. C. (2012) · Clinical and Experimental Optometry · doi:10.1111/j.1444-0938.2012.00741.x · Cited by 136
“Microglia have been reported in the subretinal space of wildtype, senescent mice,188 which is typically devoid of immune cells due to restrictions imparted by the BRB and immunosuppressants secreted by the RPE.189,190 This migration might be intended to clear accumulated age-dependent debris.”
BackgroundInfluentialThe microglia in healthy and diseased retina
Li, L., Eter, N., & Heiduschka, P. (2015) · Experimental Eye Research · doi:10.1016/j.exer.2015.04.020 · Cited by 112
Immune regulation toward immunomodulation for neuroprotection in glaucoma
Tezel, G. (2012) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2012.09.013 · Cited by 123
“Similar to other aging-related neurodegenerative diseases [87,88], continuous glial activation is recognized as a sufficient indicator of ongoing neuroinflammatory process in the glaucomatous retina and optic nerve head [6].”
Backgroundten Berge, J. C., Fazil, Z., van den Born, L. I., Wolfs, R. C. W., Schreurs, M. W. J., Dik, W. A., & Rothova, A. (2019) · Acta Ophthalmologica · doi:10.1111/aos.13899 · Cited by 118
“(Chiu et al. 2010; Jonas et al. 2012; Freedman & Iserovich 2013; Yoshida et al. 2013; Chalam et al. 2014; Rezar-Dreindl et al. 2016).”
McMenamin, P. G., Saban, D. R., & Dando, S. J. (2019) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2018.12.002 · Cited by 115
“Alterations in BrM and the RPE underlie the pathology of AMD, which is now considered to have an inflammatory or ‘para-inflammatory’ pathogenesis (Xu et al., 2009).”
BackgroundAge-related macular degeneration and changes in the extracellular matrix
Romaniuk, W. (2014) · Medical Science Monitor · doi:10.12659/msm.889887 · Cited by 120
Nonvascular retinal imaging markers of preclinical Alzheimer's disease
Snyder, P. J., Johnson, L. N., Lim, Y. Y., Santos, C. Y., Alber, J., Maruff, P. T., & Fernandez, B. M. (2016) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1016/j.dadm.2016.09.001 · Cited by 115
Leukocyte Adhesion Molecules in Diabetic Retinopathy
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“There is an accumulating body of evidence showing that leukocytes play a significant role in the pathogenesis of a number of vision-threatening retinal diseases, such as glaucoma, age-related macular degeneration, and diabetic retinopathy (DR) [1].”
Scholz, R., Caramoy, A., Bhuckory, M. B., Rashid, K., Chen, M., Xu, H., Grimm, C., & Langmann, T. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0422-5 · Cited by 111
“of microglia physiology contribute to degenerative pathologies of the retina and the entire CNS [3, 5–14].”
BackgroundSelf-citationNeuroinflammatory responses in diabetic retinopathy
Yu, Y., Chen, H., & Su, S. B. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0368-7 · Cited by 116
“Microglia together with invading choroidal macrophages significantly contribute to chronic para-inflammation present in several aging retinal pathologies [105].”
BackgroundTrophic factors in the pathogenesis and therapy for retinal degenerative diseases
Kolomeyer, A. M., & Zarbin, M. A. (2014) · Survey of Ophthalmology · doi:10.1016/j.survophthal.2013.09.004 · Cited by 119
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“Although complement remains a widely accepted pathogenic pathway in AMD, the contribution of both innate and potentially adaptive immunity is also prominent [6].”
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“In the eye they are only located in the inner retina [18,19].”
BackgroundCell-based therapeutic strategies for replacement and preservation in retinal degenerative diseases
Jones, M. K., Lü, B., Girman, S., & Wang, S. (2017) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2017.01.004 · Cited by 114
“Progression to a diseased state occurs when aging related changes are exacerbated by other disease-causing factors, such as dysregulation of inflammation or immune responses and other homeostatic processes (Xu et al., 2009).”
BackgroundSUBRETINAL DRUSENOID DEPOSIT IN AGE-RELATED MACULAR DEGENERATION
Chen, L., Messinger, J. D., Zhang, Y., Spaide, R. F., Freund, K. B., & Curcio, C. A. (2019) · Retina · doi:10.1097/iae.0000000000002657 · Cited by 110
Recharging mitochondrial batteries in old eyes. Near infra-red increases ATP
Gkotsi, D., Begum, R., Salt, T. E., Lascaratos, G., Hogg, C. R., Chau, K., Schapira, A. H. V., & Jeffery, G. (2014) · Experimental Eye Research · doi:10.1016/j.exer.2014.02.023 · Cited by 108
“…suffers progressive inflammation, extra cellular debris accumulation and cell loss (Bonnel et al., 2003; Hoh Kam et al., 2010; Jarrett et al., 2008; Xu et al., 2009), such that by 70 years approximately 30% of central rod photoreceptors are lost in the human retina and a similar number in rats at…”
BackgroundMa, W., Cojocaru, R. I., Gotoh, N., Gieser, L. M., Villasmil, R., Cogliati, T., Swaroop, A., & Wong, W. T. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.03.022 · Cited by 108
“2011) and implicating immunological influences in the overall aging phenotype of the retina (Xu et al. 2009).”
BackgroundChen, M., Forrester, J. V., & Xu, H. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022818 · Cited by 114
“macrophage/microglia subretinal migration and complement activation [19], CCL2- or CCR2deficiency appeared to modify the macrophage/microglial response.”
BackgroundInfluentialSelf-citationWong, J. H. C., Jessica, Y. W., Jobling, A. I., Brandli, A. A., Greferath, U., Fletcher, E. L., & Vessey, K. A. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1009599 · Cited by 113
“In the early stages, AMD presents as a disease of low-grade chronic inflammation, called para-inflammation, which is denoted by the perpetual recruitment and non-resolving presence of MPs (Xu et al., 2009; Leveillard et al., 2019).”
BackgroundComplement gene expression and regulation in mouse retina and retinal pigment epithelium/choroid.
Luo, C., Chen, M., & Xu, H. (2011) · PubMed Central · Cited by 107
Self-citationOn the origin of proteins in human drusen: The meet, greet and stick hypothesis
Bergen, A. A., Arya, S., Koster, C., Pilgrim, M. G., Wiatrek-Moumoulidis, D., van der Spek, P. J., Hauck, S. M., Boon, C. J. F., Emri, E., Stewart, A. J., et al. (2019) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2018.12.003 · Cited by 101
Santoro, M., Maetzler, W., Stathakos, P., Martin, H. L., Hobert, M. A., Rattay, T. W., Gasser, T., Forrester, J. V., Berg, D., Tracey, K. J., et al. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.02.018 · Cited by 107
“In other fields this general phenomenon has been described as dysregulated parainflammation (Medzhitov, 2008, Xu et al., 2009).”
BackgroundSelf-citationNeuroinflammation in Primary Open-Angle Glaucoma
Vernazza, S., Tirendi, S., Bassi, A. M., Traverso, C. E., & Saccà, S. C. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9103172 · Cited by 109
“In aging retina, glial cells and, in particular, the microglia are able to initiate an innate immune response [76] after inflammatory stimuli from oxidized proteins, lipids, and DNA.”
BackgroundNita, M., Grzybowski, A. E., Ascaso, F. J., & Huerva, V. (2014) · Mediators of Inflammation · doi:10.1155/2014/930671 · Cited by 128
“Normal, adaptive parainflammation exists in the aging retina under physiologic conditions, as a protective response against low-grade noxious waste products accumulated in Bruch’s membrane, and allows maintenance of retinal homeostasis [8, 9].”
BackgroundInfluentialThe Role of the Immune Response in Age-Related Macular Degeneration
Whitcup, S. M., Sodhi, A., Atkinson, J. P., Holers, V. M., Sinha, D., Rohrer, B., & Dick, A. D. (2013) · International Journal of Inflammation · doi:10.1155/2013/348092 · Cited by 103
“, the macula), has also been postulated to contribute to the development of AMD [11].”
BackgroundWoo, S. J., Ahn, S. J., Ahn, J., Park, K. H., & Lee, K. (2011) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.11-7784 · Cited by 97
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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