CD163+ macrophages infiltrate axon bundles of postmortem optic nerves with glaucoma

Margeta, Milica A.; Lad, Eleonora M.; Proia, Alan D.

doi:10.1007/s00417-018-4081-y

Cited by 36 publications

(33 citation statements)

References 35 publications

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“…Microglial proliferation and migration and monocyte infiltration have been reported in a number of glaucoma models and in human glaucoma (3,13,35,70,78,(92)(93)(94)(95). We demonstrate that an early increase in monocytes, but not microglia, and a late increase in microglia, but not monocytes occurs following sustained periods of OHT.…”

Section: Discussionsupporting

confidence: 61%

“…Neuroinflammation is a shared feature of glaucoma pathogenesis in human glaucoma patients (3) and animal models of glaucoma (genetic and inducible (4)). In times of stress, retinal ganglion cells are reliant on a supportive network of glial cells to provide neurotrophic and metabolic support, especially to their long, unmyelinated axons in the retina and optic nerve head.…”

Section: Introductionmentioning

confidence: 99%

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When is a control not a control? Reactive microglia occur throughout the control contralateral visual pathway in experimental glaucoma

Tribble

Kokkali

Otmani

et al. 2019

Preprint

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Background: Glaucoma remains a leading cause of irreversible blindness worldwide. Multiple animal models show retinal ganglion cell injuries that replicate features of glaucoma. In these experiments the contralateral eye is commonly used as an internal control. As in humans, in rodents and non-human primates there is significant cross-over of retinal ganglion cell axons from the ipsilateral to the contralateral side at the level of the optic chiasm which may confound findings when damage is restricted to one eye. While neuroinflammation may be a critical event that damages retinal ganglion cells and their axons during glaucoma progression the effect of unilateral damage on the contralateral visual pathway has largely been unexplored.Methods: Ocular hypertensive glaucoma was induced unilaterally or bilaterally by intracameral injection of paramagnetic beads in adult Brown Norway rats. Retinal ganglion cell neurodegeneration and dysfunction were assessed. Neuroinflammation was quantified in the retina, optic nerve head, optic nerve, lateral geniculate nucleus, and superior colliculus by high resolution imaging, and in the retina by flow cytometry and protein arrays.Results: Following ocular hypertensive stress the retinal vasculature remodels, peripheral monocytes enter the retina, and microglia become highly reactive. This effect is more marked in animals with bilateral induction of ocular hypertensive glaucoma. In rats where glaucoma was induced unilaterally there was significant microglia activation in the contralateral (control) eye. Microglial activation extended into the optic nerve and terminal visual thalami, where it was similar across hemispheres irrespective of whether ocular hypertension was unilateral or bilateral. Conclusions:Ocular hypertensive glaucoma in the rat recapitulates many of the features of human glaucoma. In this model microglia become reactive throughout the visual pathway during glaucoma pathogenesis. These effects are not isolated to the experimental eye and its pathway and significant neuroinflammation occurs in the contralateral 'control' eye and pathway. These data suggest that caution is warranted when using the contralateral eye as control in unilateral models of glaucomatous damage.

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Section: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

When is a control not a control? Reactive microglia occur throughout the control contralateral visual pathway in experimental glaucoma

Tribble

Kokkali

Otmani

et al. 2019

Preprint

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“…In addition to microglia, TREM2 is also expressed by peripheral myeloid cells (monocytes and macrophages). 18 Notably, macrophages are abundantly present in the conventional outflow pathway 65 and have been implicated in IOP regulation after selective laser trabeculoplasty. 66 Further research will be necessary to validate our genetic findings and explore the possible role of TREM2 in IOP regulation.…”

Section: Discussionmentioning

confidence: 99%

Association of APOE With Primary Open-Angle Glaucoma Suggests a Protective Effect for APOE ε4

Margeta

Letcher

Igo

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Prior studies have demonstrated that microglial activation is involved in the pathogenesis of primary open-angle glaucoma (POAG). Here we sought to identify genetic associations between POAG and variants in APOE and TREM2, genes associated with Alzheimer disease (AD) that critically regulate microglial neurodegenerationassociated molecular signature. METHODS. APOE genotypes were called using imputed data from the NEIGHBOR consortium (2120 POAG cases, 2262 controls) and a second cohort from the Massachusetts Eye and Ear Infirmary (MEEI; 486 cases, 344 controls). TREM2 coding variants were genotyped by means of the Illumina HumanExome BeadArray. The data set was analyzed for association with POAG overall, as well as the high-tension glaucoma (HTG) and normaltension glaucoma (NTG) subgroups, using logistic regression adjusting for age and sex. RESULTS. In the combined NEIGHBOR-MEEI data set, significant association was observed for APOE ε4 in POAG overall (odds ratio [OR], 0.83; 95% confidence interval [CI], 0.74-0.94; P = 0.0022) and in both the HTG subgroup (OR, 0.81; 95% CI, 0.70-0.94; P = 0.0052) and NTG subgroup (OR, 0.71; 95% CI, 0.58-0.87; P = 0.0014). A rare TREM2 variant (A105V) was found only in HTG cases (3 of 2863 cases) and in none of the controls (P = 0.03). Three TREM2 rare variants associated with AD were not significantly associated with POAG (P > 0.05). CONCLUSIONS. We have found that the APOE ε4 allele is associated with a reduced risk of POAG. Interestingly, the same allele is adversely associated with AD, suggesting a mechanistic difference between neurodegenerative diseases of the eye and the brain. TREM2 variants associated with AD did not significantly contribute to POAG risk.

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“…Among the several cells and inflammatory mediators that are important for the ocular surface diseases, we found the number of research papers following this decreasing order: dendritic cells (19) > IL6 (15) > IL17 (8) > CD4 + and CD8 + T cells together (7). The eight diseases that matched the inclusion criteria of the study mentioned in the method section are: contact lens wear [15][16][17][18][19][20], corneal graft rejection [21][22][23], dry eye [6,[24][25][26][27][28][29][30][31][32][33][34], glaucoma [35][36][37][38][39][40][41][42], Graft-vs-host (GvHD) [43,44], keratitis [45][46][47], scleritis [48][49][50], and Sjögren's syndrome [28,29,[32][33][34][51][52][53]. This is a combination of different ocular surface disorders, the range of w...…”

Section: Dendritic Cells Are the Major Immune Cells Responsible For Omentioning

confidence: 98%

The Innate Immune Cell Profile of the Cornea Predicts the Onset of Ocular Surface Inflammatory Disorders

Palomar

Montolío

Cegoñino

et al. 2019

JCM

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Ocular surface inflammatory disorder (OSID) is a spectrum of disorders that have features of several etiologies whilst displaying similar phenotypic signs of ocular inflammation. They are complicated disorders with underlying mechanisms related to several autoimmune disorders, such as rheumatoid arthritis (RA), Sjögren’s syndrome, and systemic lupus erythematosus (SLE). Current literature shows the involvement of both innate and adaptive arms of the immune system in ocular surface inflammation. The ocular surface contains distinct components of the immune system in the conjunctiva and the cornea. The normal conjunctiva epithelium and sub-epithelial stroma contains resident immune cells, such as T cells, B cells (adaptive), dendritic cells, and macrophages (innate). The relative sterile environment of the cornea is achieved by the tolerogenic properties of dendritic cells in the conjunctiva, the presence of regulatory lymphocytes, and the existence of soluble immunosuppressive factors, such as the transforming growth factor (TGF)-β and macrophage migration inhibitory factors. With the presence of both innate and adaptive immune system components, it is intriguing to investigate the most important leukocyte population in the ocular surface, which is involved in immune surveillance. Our meta-analysis investigates into this with a focus on both infectious (contact lens wear, corneal graft rejection, Cytomegalovirus, keratitis, scleritis, ocular surgery) and non-infectious (dry eye disease, glaucoma, graft-vs-host disease, Sjögren’s syndrome) situations. We have found the predominance of dendritic cells in ocular surface diseases, along with the Th-related cytokines. Our goal is to improve the knowledge of immune cells in OSID and to open new dimensions in the field. The purpose of this study is not to limit ourselves in the ocular system, but to investigate the importance of dendritic cells in the disorders of other mucosal organs (e.g., lungs, gut, uterus). Holistically, we want to investigate if this is a common trend in the initiation of any disease related to the mucosal organs and find a unified therapeutic approach. In addition, we want to show the power of computational approaches to foster a collaboration between computational and biological science.

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CD163+ macrophages infiltrate axon bundles of postmortem optic nerves with glaucoma

Abstract: The increase in CD163+ cell number in eyes with mild and severe glaucoma is the first demonstration of macrophage infiltration in glaucomatous human optic nerves. This finding supports a role for macrophages in glaucoma pathogenesis and progression.

Cited by 36 publications

References 35 publications

When is a control not a control? Reactive microglia occur throughout the control contralateral visual pathway in experimental glaucoma

When is a control not a control? Reactive microglia occur throughout the control contralateral visual pathway in experimental glaucoma

Association of APOE With Primary Open-Angle Glaucoma Suggests a Protective Effect for APOE ε4

The Innate Immune Cell Profile of the Cornea Predicts the Onset of Ocular Surface Inflammatory Disorders

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