bims-mideyd 2024-03-10 papers

Issue of 2024‒03‒10
three papers selected by
Raji Shyam, Indiana University Bloomington

Int Immunopharmacol. 2024 Mar 07. pii: S1567-5769(24)00329-1. [Epub ahead of print]130 111811

TRPV4 antagonist suppresses retinal ganglion cell apoptosis by regulating the activation of CaMKII and TNF-α expression in a chronic ocular hypertension rat model.

Wenhui Liu, Wenzhe Zhang, Chen Wang, Jiarun Song, Kaiyue Li, Xia Zhang, Xinyi Wu, Hui Guo.

Glaucoma is characterized by a progressive loss of retinal ganglion cells (RGCs), leading to irreversible visual function impairment. Sustained increase in intraocular pressure represents a major risk factor for glaucoma, yet the underlying mechanisms of RGC apoptosis induced by intraocular pressure remains unclear. This study aims to investigate the role of TRPV4 in RGC apoptosis in a rat model of chronic ocular hypertension (COH) and the underlying molecular mechanism. In the COH rat models, we evaluated the visual function, retinal pathological changes and RGC apoptosis. TRPV4 expression and downstream signaling molecules were also detected. We found that RGC density decreased and RGC apoptosis was induced in COH eyes compared with control eyes. TRPV4 expression increased significantly in response to elevated IOP. TRPV4 inhibition by the TRPV4 antagonist HC-067047 (HC-067) suppressed RGC apoptosis and protected visual function. HC-067 treatment upregulated the phosphorylation of CaMKII in both control and COH eyes. Finally, HC-067 treatment suppressed the production of TNF-α induced by ocular hypertension. The TRPV4 antagonist HC-067 might suppress RGC apoptosis by regulating the activation of CaMKII and inhibiting the production of TNF-α in the COH model. This indicated that TRPV4 antagonists may be a potential and novel therapeutic strategy for glaucoma.

Keywords: Apoptosis; CaMKII; Glaucoma; Retinal ganglion cells; TRPV4; Tumor necrosis factor-α

DOI: https://doi.org/10.1016/j.intimp.2024.111811

J Neuroinflammation. 2024 Mar 05. 21(1): 64

The contribution of pattern recognition receptor signalling in the development of age related macular degeneration: the role of toll-like-receptors and the NLRP3-inflammasome.

Alice Brandli, Kirstan A Vessey, Erica L Fletcher.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss, characterised by the dysfunction and death of the photoreceptors and retinal pigment epithelium (RPE). Innate immune cell activation and accompanying para-inflammation have been suggested to contribute to the pathogenesis of AMD, although the exact mechanism(s) and signalling pathways remain elusive. Pattern recognition receptors (PRRs) are essential activators of the innate immune system and drivers of para-inflammation. Of these PRRs, the two most prominent are (1) Toll-like receptors (TLR) and (2) NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)-inflammasome have been found to modulate the progression of AMD. Mutations in TLR2 have been found to be associated with an increased risk of developing AMD. In animal models of AMD, inhibition of TLR and NLRP3 has been shown to reduce RPE cell death, inflammation and angiogenesis signalling, offering potential novel treatments for advanced AMD. Here, we examine the evidence for PRRs, TLRs2/3/4, and NLRP3-inflammasome pathways in macular degeneration pathogenesis.

Keywords: Age related macular degeneration; Innate immunity; Microglia; NLRP3; NOD-1 like; P2 × 7; Pattern recognition receptor; Retinal degeneration; Toll-like receptors

DOI: https://doi.org/10.1186/s12974-024-03055-1

FASEB J. 2024 Mar 15. 38(5): e23522

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function.

Catharina R Grubaugh, Anuradha Dhingra, Binu Prakash, Diego Montenegro, Janet R Sparrow, Lauren L Daniele, Christine A Curcio, Brent A Bell, M Mahmood Hussain, Kathleen Boesze-Battaglia.

Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal aging or age-related disease triggers lipid accumulation within the RPE, on Bruch's membrane (BrM), and in the subretinal space. In its role as a hub for lipid trafficking into and out of the neural retina, the RPE packages a significant amount of lipid into lipid droplets for storage and into apolipoprotein B (APOB)-containing lipoproteins (Blps) for export. Microsomal triglyceride transfer protein (MTP), encoded by the MTTP gene, is essential for Blp assembly. Herein we test the hypothesis that MTP expression in the RPE is essential to maintain lipid balance and retinal function using the newly generated RPEΔMttp mouse model. Using non-invasive ocular imaging, electroretinography, and histochemical and biochemical analyses we show that genetic depletion of Mttp from the RPE results in intracellular lipid accumulation, increased photoreceptor-associated cholesterol deposits, and photoreceptor cell death, and loss of rod but not cone function. RPE-specific reduction in Mttp had no significant effect on plasma lipids and lipoproteins. While APOB was decreased in the RPE, most ocular retinoids remained unchanged, with the exception of the storage form of retinoid, retinyl ester. Thus suggesting that RPE MTP is critical for Blp synthesis and assembly but is not directly involved in plasma lipoprotein metabolism. These studies demonstrate that RPE-specific MTP expression is necessary to establish and maintain retinal lipid homeostasis and visual function.

Keywords: APOB-containing lipoprotein; cholesterol; lipid steatosis; lipoid degeneration; microsomal triglyceride transfer protein; retinal degeneration; retinal function; retinal pigment epithelium; subretinal deposits

DOI: https://doi.org/10.1096/fj.202302491R