Cholesterol regulates polymodal sensory transduction in Müller glia

Lakk, Mónika; Yarishkin, Oleg; Baumann, Jackson M.; Iuso, Anthony; Križaj, David

doi:10.1002/glia.23213

Cited by 43 publications

(45 citation statements)

References 95 publications

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“…S1). We observed the highest levels of CAV1 protein expression in Müller glia cells and retinal blood vessels, which agrees with previous studies (17,22,24,35,36). In retinal tissue sections, Müller glia have a unique morphology where their cellular processes span the retina from inner limiting membrane at the edge of the RGC layer to the outer limiting membrane at the edge of the outer nuclear layer (ONL); whereas, the retinal vasculature appears as discrete vessel crosssections in the plexiform synaptic layers of the retina (Fig.…”

Section: Neural Retinal Cav1 Depletion Primarily Targets Retinal Müllsupporting

confidence: 93%

Neuroretinal-derived caveolin-1 promotes endotoxin-induced inflammation in the murine retina

Gurley

Gmyrek

McClellan

et al. 2020

Preprint

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Chronic ocular inflammation is associated with many retinal degenerative diseases that result in vision loss. The immune-privileged environment and complex organization of retinal tissue allow for the retina’s essential role in visual function processes, yet confound inquiries into cell-specific inflammatory effects that lead to retinal dysfunction and degeneration. Caveolin-1 (Cav1) is an integral membrane protein expressed in many retinal cell populations and has been implicated in retinal immune regulation. However, the direction (i.e., promotion or inhibition) in which Cav1 regulates inflammatory processes in the retina (as well as in other tissues) remains unclear. Previously, we showed that global-Cav1 depletion in the retina paradoxically resulted in reduced retinal inflammatory cytokine production with concurrent elevated retinal immune cell infiltration. We hypothesized that our previous results could be explained by cell-specific Cav1 functions in the retina. Here, we utilized our Chx10 (visual system homeobox 2)-Cre knockout model to deplete Cav1 specifically in the neural retinal (NR) compartment in order to clarify the role of neural retinal-specific Cav1 (NR-Cav1) in the retinal immune response to intravitreal LPS (lipopolysaccharide) challenge. Our data support that neural retinal-derived Cav1 promotes retinal tissue inflammation as Chx10-mediated Cav1 depletion was sufficient to suppress both retinal cytokine production and immune cell infiltration following inflammatory stimulation. Additionally, we identify Traf3 (tumor necrosis factor (TNF) receptor-associated factor 3) as a highly expressed potential immune modulator in retinal tissue that is upregulated with NR-Cav1 depletion. Furthermore, this study highlights the importance for understanding the role of Cav1 (and other proteins) in cell-specific contexts.

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Section: Neural Retinal Cav1 Depletion Primarily Targets Retinal Müllsupporting

confidence: 93%

Neuroretinal-derived caveolin-1 promotes endotoxin-induced inflammation in the murine retina

Gurley

Gmyrek

McClellan

et al. 2020

Preprint

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“…) could modulate BRB permeability in the presence of dyslipidaemic stress (Lakk et al . ), with TRPV4‐dependent junctional remodelling playing a role in the loss of vascular autoregulation associated with focal fluid leakage, angiogenesis, oedema formation and transendothelial invasion of monocytes in retinal pathologies such as glaucoma, diabetic retinopathy, ischaemia and blast trauma (Navaratna et al . ; Klaassen et al .…”

Section: Discussionmentioning

confidence: 99%

“…; Lakk et al . ), its effects on vascular mechanosensing are likely to be influenced by changes in the expression of CYP450 (CYP2C; CYP2J) enzymes and translocation of TRPV4 from submembrane reserve pools (White et al . ; Redmon et al .…”

Section: Discussionmentioning

confidence: 99%

Calcium influx through TRPV4 channels modulates the adherens contacts between retinal microvascular endothelial cells

Phuong

Redmon

Yarishkin

et al. 2017

The Journal of Physiology

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The identity of microvascular endothelial (MVE) mechanosensors that sense blood flow in response to mechanical and chemical stimuli and regulate vascular permeability in the retina is unknown. Using immunohistochemistry, calcium imaging, electrophysiology, impedance measurements and vascular permeability assays, we show that the transient receptor potential isoform 4 (TRPV4) plays a major role in Ca /cation signalling, cytoskeletal remodelling and barrier function in retinal microvasculature in vitro and in vivo. Human retinal MVE cells (HrMVECs) predominantly expressed Trpv1 and Trpv4 transcripts, and TRPV4 was broadly localized to the plasma membrane of cultured cells and intact blood vessels in the inner retina. Treatment with the selective TRPV4 agonist GSK1016790A (GSK101) activated a nonselective cation current, robustly elevated [Ca ] and reversibly increased the permeability of MVEC monolayers. This was associated with disrupted organization of endothelial F-actin, downregulated expression of occludin and remodelling of adherens contacts consisting of vascular endothelial cadherin (VE-cadherin) and β-catenin. In vivo, GSK101 increased the permeability of retinal blood vessels in wild type but not in TRPV4 knockout mice. Agonist-evoked effects on barrier permeability and cytoskeletal reorganization were antagonized by the selective TRPV4 blocker HC 067047. Human choroidal endothelial cells expressed lower TRPV4 mRNA/protein levels and showed less pronounced agonist-evoked calcium signals compared to MVECs. These findings indicate a major role for TRPV4 in Ca homeostasis and barrier function in human retinal capillaries and suggest that TRPV4 may differentially contribute to the inner vs. outer blood-retinal barrier function.

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“…, ) and cholesterol (Lakk et al . ), endoplasmic reticulum Ca 2+ store repletion (TRPC1; Szikra et al . ; Molnar et al .…”

Section: Discussionmentioning

confidence: 99%

Mouse retinal ganglion cell signalling is dynamically modulated through parallel anterograde activation of cannabinoid and vanilloid pathways

Noel

Lakk

et al. 2017

The Journal of Physiology

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How retinal ganglion cells (RGCs) process and integrate synaptic, mechanical, swelling stimuli with light inputs is an area of intense debate. The nociceptive cation channel TRPV1 (transient receptor potential vanilloid type 1) modulates RGC Ca signals and excitability yet the proportion of RGCs that express it remains unclear. Furthermore, TRPV1's response to endocannabinoids (eCBs), the putative endogenous retinal activators, is unknown, as is the potential modulation by cannabinoid receptors (CBRs). The density of TRPV1-expressing RGCs in the Ai9:Trpv1 reporter mouse peaked in the mid-peripheral retina. TRPV1 agonists including capsaicin (CAP) and the eCBs anandamide and N-arachidonoyl-dopamine elevated [Ca ] in 30-40% of wild-type RGCs, with effects suppressed by TRPV1 antagonists capsazepine (CPZ) and BCTC ((4-(3-chloro-2-pyridinyl)-N-[4-(1,1-dimethylethyl)phenyl]-1-piperazinecarboxamide), and lacking in Trpv1 cells. The cannabinoid receptor type 1 (CB1R) colocalized with TRPV1:tdTomato expression. Its agonists 2-arachidonoylglycerol (2-AG) and WIN55,122 inhibited CAP-induced [Ca ] signals in adult, but not early postnatal, RGCs. The suppressive effect of 2-AG on TRPV1 activation was emulated by positive modulators of the protein kinase A (PKA) pathway, inhibited by the CB1R antagonist rimonabant and G uncoupler pertussis toxin, and absent in Cnr1 RGCs. We conclude that TRPV1 is a modulator of Ca homeostasis in a subset of RGCs that show non-uniform distribution across the mouse retina. Non-retrograde eCB-mediated modulation of RGC signalling involves a dynamic push-pull between direct TRPV1 activation and PKA-dependent regulation of channel inactivation, with potential functions in setting the bandwidth of postsynaptic responses, sensitivity to mechanical/excitotoxic stress and neuroprotection.

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Cholesterol regulates polymodal sensory transduction in Müller glia

Cited by 43 publications

References 95 publications

Neuroretinal-derived caveolin-1 promotes endotoxin-induced inflammation in the murine retina

Neuroretinal-derived caveolin-1 promotes endotoxin-induced inflammation in the murine retina

Calcium influx through TRPV4 channels modulates the adherens contacts between retinal microvascular endothelial cells

Mouse retinal ganglion cell signalling is dynamically modulated through parallel anterograde activation of cannabinoid and vanilloid pathways

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