Association of Toll-like Receptor 4 Gene Polymorphisms in Japanese Subjects With Primary Open-Angle, Normal-Tension, and Exfoliation Glaucoma

Takano, Yoshinao; Shi, Dong; Shimizu, Ai; Funayama, Tomoyo; Mashima, Yukihiko; Yasuda, Noriko; Fukuchi, Takeo; Abe, Haruki; Ideta, Hidenao; Zheng, Xiaodong; Shiraishi, Atsushi; Ohashi, Yuichi; Nishida, Kohji; Nakazawa, Toru; Fuse, Nobuo

doi:10.1016/j.ajo.2012.03.050

Cited by 53 publications

(42 citation statements)

References 29 publications

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“…TLR pathways have been implicated in the pathology of various neurodegenerations [19] as well as in glaucoma [20], [21]. We determined that LPS administration in DBA/2J mice led to significant upregulation of the Myd88-dependent pathway genes (Myd88, Traf6, cJun) which are downstream targets of TLR4 (the main receptor for LPS) in retinas of LPS treated mice ( Figure 3a ).…”

Section: Resultsmentioning

confidence: 94%

Oral Microbiome Link to Neurodegeneration in Glaucoma

Astafurov¹,

Elhawy²,

Ren³

et al. 2014

PLoS ONE

105

118

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BackgroundGlaucoma is a progressive optic nerve degenerative disease that often leads to blindness. Local inflammatory responses are implicated in the pathology of glaucoma. Although inflammatory episodes outside the CNS, such as those due to acute systemic infections, have been linked to central neurodegeneration, they do not appear to be relevant to glaucoma. Based on clinical observations, we hypothesized that chronic subclinical peripheral inflammation contributes to neurodegeneration in glaucoma.MethodsMouthwash specimens from patients with glaucoma and control subjects were analyzed for the amount of bacteria. To determine a possible pathogenic mechanism, low-dose subcutaneous lipopolysaccharide (LPS) was administered in two separate animal models of glaucoma. Glaucomatous neurodegeneration was assessed in the retina and optic nerve two months later. Changes in gene expression of toll-like receptor 4 (TLR4) signaling pathway and complement as well as changes in microglial numbers and morphology were analyzed in the retina and optic nerve. The effect of pharmacologic blockade of TLR4 with naloxone was determined.FindingsPatients with glaucoma had higher bacterial oral counts compared to control subjects (p<0.017). Low-dose LPS administration in glaucoma animal models resulted in enhancement of axonal degeneration and neuronal loss. Microglial activation in the optic nerve and retina as well as upregulation of TLR4 signaling and complement system were observed. Pharmacologic blockade of TLR4 partially ameliorated the enhanced damage.ConclusionsThe above findings suggest that the oral microbiome contributes to glaucoma pathophysiology. A plausible mechanism by which increased bacterial loads can lead to neurodegeneration is provided by experiments in animal models of the disease and involves activation of microglia in the retina and optic nerve, mediated through TLR4 signaling and complement upregulation. The finding that commensal bacteria may play a role in the development and/or progression of glaucomatous pathology may also be relevant to other chronic neurodegenerative disorders.

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Section: Resultsmentioning

confidence: 94%

Oral Microbiome Link to Neurodegeneration in Glaucoma

Astafurov¹,

Elhawy²,

Ren³

et al. 2014

PLoS ONE

105

118

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“…21, 22, 27, 28 So we examined the protein expression of TLR4 in the retina of WT, EAAC1 KO mice and candesartan-treated (1 week from 5 W) EAAC1 KO mice. A significant increase of TLR4 expression was observed in untreated EAAC1 KO mice, but candesartan treatment suppressed this increase (Figure 5c).…”

Section: Resultsmentioning

confidence: 99%

Renin–angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma

et al. 2014

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Glaucoma, one of the leading causes of irreversible blindness, is characterized by progressive degeneration of optic nerves and retinal ganglion cells (RGCs). In the mammalian retina, excitatory amino acid carrier 1 (EAAC1) is expressed in neural cells, including RGCs, and the loss of EAAC1 leads to RGC degeneration without elevated intraocular pressure (IOP). In the present study, we found that expressions of angiotensin II type 1 receptor (AT1-R) and Toll-like receptor 4 (TLR4) are increased in RGCs and retinal Müller glia in EAAC1-deficient (KO) mice. The orally active AT1-R antagonist candesartan suppressed TLR4 and lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expressions in the EAAC1 KO mouse retina. Sequential in vivo retinal imaging and electrophysiological analysis revealed that treatment with candesartan was effective for RGC protection in EAAC1 KO mice without affecting IOP. In cultured Müller glia, candesartan suppressed LPS-induced iNOS production by inhibiting the TLR4-apoptosis signal-regulating kinase 1 pathway. These results suggest that the renin–angiotensin system is involved in the innate immune responses in both neural and glial cells, which accelerate neural cell death. Our findings raise intriguing possibilities for the management of glaucoma by utilizing widely prescribed drugs for the treatment of high blood pressure, in combination with conventional treatments to lower IOP.

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“…22 Recently, Takano and colleagues not only confirmed the association of TLR4 polymorphisms with NTG in another Japanese cohort but also showed that they may play a role in the pathogenesis of POAG and pseudoexfoliation glaucoma. 30 In addition, in another study by Chen and co-workers, 31 TLR4 SNP rs7037117 was reported to be associated with late-onset POAG in a Southern Chinese population but not in the Northern Chinese. However, similar to our findings, the TLR4 polymorphisms were not found to be significantly associated with the risk of NTG in the South Korean population, 32 suggesting that the role of polymorphism(s) in TLR4 and glaucoma may be ethnic specific.…”

Section: Discussionmentioning

confidence: 97%

Analysis of toll-like receptor rs4986790 polymorphism in Saudi patients with primary open angle glaucoma

Abu-Amero

Kondkar

Mousa

et al. 2016

Ophthalmic Genetics

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Among cases, the normal pattern (A/A) was detected in 70 (82.4%) of the subjects, A/G in 14 (16.5%) and G/G in one subject only (1.2%). Among controls, prevalence of the genotype (A/A) was detected in 86 (90.5%), the (A/G) genotype in 8 (8.4%) and homozygous mutated genotype (G/G) in 1 (1.1%) subjects. Comparing cases to controls, the odds ratio of having heterozygous mutation (A/G) was 2.15 [95% CI: 0.853-5.417], which was not significant (p = 0.114). The odds ratio of having homozygous mutation (G/G) was 1.22 [95% CI: 0.075-19.99], which was statistically non-significant (p = 0.568). Likewise, the presence of the mutated allele (G) was non-significantly different between cases and controls (p = 0.154). Comparing cases to controls as regards co-morbidity with other systemic diseases, there were no statistically significant differences between groups in all assessed diseases except for a family history of glaucoma (p = 0.014) Conclusions: In conclusion, we could not detect any direct link between genotypes or allele frequencies of SNP rs4986790 in the TLR4 gene and POAG. In contrast, genotype (A/A) may be protective against POAG especially among individuals with no family history of glaucoma.

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Association of Toll-like Receptor 4 Gene Polymorphisms in Japanese Subjects With Primary Open-Angle, Normal-Tension, and Exfoliation Glaucoma

Cited by 53 publications

References 29 publications

Oral Microbiome Link to Neurodegeneration in Glaucoma

Oral Microbiome Link to Neurodegeneration in Glaucoma

Renin–angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma

Analysis of toll-like receptor rs4986790 polymorphism in Saudi patients with primary open angle glaucoma

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