Constitutive Expression of HCA<sub>2</sub>in Human Retina and Primary Human Retinal Pigment Epithelial Cells

Yu, Alice L.; Birke, Kerstin; Lorenz, Reinhard; Welge–Lüßen, Ulrich

doi:10.3109/02713683.2013.848900

Cited by 3 publications

(2 citation statements)

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“…MMF is an agonist of the HCAR2 receptor, which is expressed in peripheral macrophages and microglia in mouse brain 14. Although expression of Hcar2 has been reported in the RPE of mouse retina, expression in retinal microglia has not been reported previously to our knowledge 40,41. In this study, Hcar2 mRNA was detected in the neural retina and was upregulated by light exposure.…”

Section: Discussionmentioning

confidence: 50%

Monomethyl Fumarate Protects the Retina From Light-Induced Retinopathy

Jiang

Ryals

Huang

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Purpose We determine if monomethyl fumarate (MMF) can protect the retina in mice subjected to light-induced retinopathy (LIR). Methods Albino BALB/c mice were intraperitoneally injected with 50 to 100 mg/kg MMF before or after exposure to bright white light (10,000 lux) for 1 hour. Seven days after light exposure, retinal structure and function were evaluated by optical coherence tomography (OCT) and electroretinography (ERG), respectively. Retinal histology also was performed to evaluate photoreceptor loss. Expression levels of Hcar2 and markers of microglia activation were measured by quantitative PCR (qPCR) in the neural retina with and without microglia depletion. At 24 hours after light exposure, retinal sections and whole mount retinas were stained with Iba1 to evaluate microglia status. The effect of MMF on the nuclear factor kB subunit 1 (NF-kB) and Nrf2 pathways was measured by qPCR and Western blot. Results MMF administered before light exposure mediated dose-dependent neuroprotection in a mouse model of LIR. A single dose of 100 mg/kg MMF fully protected retinal structure and function without side effects. Expression of the Hcar2 receptor and the microglia marker Cd14 were upregulated by LIR, but suppressed by MMF. Depleting microglia reduced Hcar2 expression and its upregulation by LIR. Microglial activation, upregulation of proinflammatory genes ( Nlrp3 , Caspase1 , Il-1β , Tnf-α ), and upregulation of antioxidative stress genes ( Hmox1 ) associated with LIR were mitigated by MMF treatment. Conclusions MMF can completely protect the retina from LIR in BALB/c mice. Expression of Hcar2 , the receptor of MMF, is microglia-dependent in the neural retina. MMF-mediated neuroprotection was associated with attenuation of microglia activation, inflammation and oxidative stress in the retina.

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Section: Discussionmentioning

confidence: 50%

Monomethyl Fumarate Protects the Retina From Light-Induced Retinopathy

Jiang

Ryals

Huang

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…It is endogenously activated by β-hydroxybutyrate (BHB), a ketone body that also exerts an interesting protective effect in different experimental models of neuropathic pain [33]. HCA 2 receptor is constitutively expressed in all the retinal layers, including retinal pigment epithelial (RPE) cells [4,5,34]. These cells play a critical role in the modulation of the immune and inflammatory responses in retinal physiological conditions, particularly diabetic retinopathy [35–38].…”

Section: Discussionmentioning

confidence: 99%

The activation of retinal HCA2 receptors by systemic beta-hydroxybutyrate inhibits diabetic retinal damage through reduction of endoplasmic reticulum stress and the NLRP3 inflammasome

et al. 2019

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ObjectiveThe role of the hydroxycarboxylic acid receptor 2 (HCA2) in the retinal damage induced by diabetes has never been explored. In this context, the present study highlights an upregulation of retinal HCA2 receptors in diabetic C57BL6J mice. Moreover, we illustrate that HCA2 receptors exert an anti-inflammatory effect on the retinal damage induced by diabetes when activated by the endogenous ligand β-hydroxybutyrate,MethodologySeven-to-10-week-old C57BL6J mice were rendered diabetic by a single intraperitoneal injection of streptozotocin (75 mg/kg of body weight) and monitored intermittently over a 10-week period extending from the initial diabetes assessment. Mice with a fasting blood glucose level higher than 250 mg/dl for 2 consecutive weeks after streptozotocin injection were treated twice a week with intraperitoneal injections of 25-50-100 mg/kg β-hydroxybutyrate.ResultsInterestingly, while the retinal endoplasmic reticulum stress markers (pPERK, pIRE1, ATF-6α) were elevated in diabetic C57BL6J mice, their levels were significantly reduced by the systemic intraperitoneal treatment with 50 mg/kg and 100 mg/kg β-hydroxybutyrate. These mice also exhibited high NLRP3 inflammasome activity and proinflammatory cytokine levels. In fact, the elevated levels of retinal NLRP3 inflammasome activation markers (NLRP3, ASC, caspase-1) and of the relative proinflammatory cytokines (IL-1β, IL-18) were significantly reduced by 50 mg/kg and 100 mg/kg β-hydroxybutyrate treatment. These doses also reduced the high apoptotic cell number exhibited by the diabetic mice in the retinal outer nuclear layer (ONL) and increased the ONL low connexin 43 expression, leading to an improvement in retinal permeability and homeostasis.ConclusionsThese data suggest that the systemic treatment of diabetic C57BL6J mice with BHB activates retinal HCA2 and inhibits local damage.

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Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2

et al. 2016

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Constitutive Expression of HCA₂in Human Retina and Primary Human Retinal Pigment Epithelial Cells

Abstract: Based on these results, HCA2 appears to be constitutively expressed in human retina and in primary human RPE cells. Although its functional role is still unknown, HCA2 may be potentially involved in the pathogenesis of various retinopathies and may offer a new therapeutic target.

Cited by 3 publications

References 32 publications

Monomethyl Fumarate Protects the Retina From Light-Induced Retinopathy

Monomethyl Fumarate Protects the Retina From Light-Induced Retinopathy

The activation of retinal HCA2 receptors by systemic beta-hydroxybutyrate inhibits diabetic retinal damage through reduction of endoplasmic reticulum stress and the NLRP3 inflammasome

Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2

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Constitutive Expression of HCA2in Human Retina and Primary Human Retinal Pigment Epithelial Cells

Abstract: Based on these results, HCA2 appears to be constitutively expressed in human retina and in primary human RPE cells. Although its functional role is still unknown, HCA2 may be potentially involved in the pathogenesis of various retinopathies and may offer a new therapeutic target.

Cited by 3 publications

References 32 publications

Monomethyl Fumarate Protects the Retina From Light-Induced Retinopathy

Monomethyl Fumarate Protects the Retina From Light-Induced Retinopathy

The activation of retinal HCA2 receptors by systemic beta-hydroxybutyrate inhibits diabetic retinal damage through reduction of endoplasmic reticulum stress and the NLRP3 inflammasome

Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2

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Constitutive Expression of HCA₂in Human Retina and Primary Human Retinal Pigment Epithelial Cells