TRPV4 channels promote vascular permeability in retinal vascular disease

Nishinaka, Anri; Tanaka, Mizuki; Ohara, Kentaro; Sugaru, Eiji; Shishido, Yuji; Moriguchi, Yukiko; Toui, Amane; Nakamura, Shinsuke; Shimada, Kaoru; Watanabe, Shuzo; Hara, Hideaki; Shimazawa, Masamitsu

doi:10.1016/j.exer.2023.109405

Cited by 8 publications

(5 citation statements)

References 30 publications

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“…Such infiltration was evident at 48h post-OHT induction, as confirmed by abundant CD45 + CD11b + cells in the retina and optic nerve (Figure 9), and strongly correlated with unexpectedly high for such a mild injury, levels of cytokines. Importantly, monocyte and leukocyte infiltration is implicated in various retinal degenerations, including OHT-induced ischemiareperfusion [104] , AMD [105] and glaucoma [86,106].…”

Section: Discussionmentioning

confidence: 99%

Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes

Spurlock,

An,

Reshetnikova

et al. 2023

Preprint

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Dysfunction and selective loss of retinal ganglion cells (RGCs) is a known cause of vision loss in glaucoma and other neuropathies where ocular hypertension (OHT) is the major risk factor. We investigated the impact of transient non-ischemic OHT spikes (spOHT) on RGC function and viability in vivo to identify cellular pathways linking low-grade repetitive mechanical stress to RGC pathology. We found that repetitive spOHT had an unexpectedly high impact on intraocular homeostasis and RGC viability, while exposure to steady OHT (stOHT) of similar intensity and duration failed to induce pathology. The repetitive spOHT induced a rapid activation of the inflammasome, marked by the upregulation of NLRP1, NLRP3, AIM2, caspases -1, -3/7, -8, gasdermin D (GsdmD) and the release of interleukin-1β (IL-1β) and other cytokines into the vitreous. Similar effects were also detected after 5 weeks of exposure to chronic OHT in an induced glaucoma model. The onset of these immune responses in both spOHT and glaucoma models preceded a 50% deficit in pattern electroretinograms (PERG) amplitude, and significant loss of RGCs at 7 days post-injury. Inactivation of inflammasome complexes in NLRP1-/- , Casp1-/- and GsdmD-/- knockout animals, significantly suppressed the spOHT induced inflammatory response and protected RGCs. Our results demonstrate that mechanical stress produced by acute repetitive spOHT or chronic OHT is mechanistically linked to inflammasome activation, which leads to RGC dysfunction and death.

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Section: Discussionmentioning

confidence: 99%

Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes

Spurlock,

An,

Reshetnikova

et al. 2023

Preprint

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“…These are integrated into Signal 1, which facilitates the transcriptional induction of inflammasome components via TLR, TNF, IL-1, C5a receptors, and alarmins, and Signal 2, which facilitates complex assembly in response to lysosomal damage and extracellular ATP and K + elevations via Panx1-P2X4/7 activation [68][69][70][71][72]. Abundant evidence from the literature supports a model in which the spOHT-induced stimulation of the mechanosensitive Ca 2+ channels, Panx1 [33,73,74], Piezo-1 [75], and transient receptor potential (TRP) vanilloid TRPV1 and TRPV4 [3,76,77] channels in neural cell plasma membrane initiates pro-inflammatory signaling [66,[78][79][80]. Although only Piezo1 was confirmed as an interaction partner of Panx1 [39,81,82], it is feasible to suggest that a synergistic activation of all these channels through repetitive IOP spikes exacerbates Panx1 opening due to the increase in intracellular Ca 2+ , causing the over-activation of the inflammasome due to subsequent ATP release [34].…”

Section: Mechanosensor Signaling Drives Inflammasome Activationmentioning

confidence: 99%

The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes

Spurlock,

An,

Reshetnikova

et al. 2023

Cells

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The dysfunction and selective loss of retinal ganglion cells (RGCs) is a known cause of vision loss in glaucoma and other neuropathies, where ocular hypertension (OHT) is the major risk factor. We investigated the impact of transient non-ischemic OHT spikes (spOHT) on RGC function and viability in vivo to identify cellular pathways linking low-grade repetitive mechanical stress to RGC pathology. We found that repetitive spOHT had an unexpectedly high impact on intraocular homeostasis and RGC viability, while exposure to steady OHT (stOHT) of a similar intensity and duration failed to induce pathology. The repetitive spOHT induced the rapid activation of the inflammasome, marked by the upregulation of NLRP1, NLRP3, AIM2, caspases -1, -3/7, -8, and Gasdermin D (GSDMD), and the release of interleukin-1β (IL-1β) and other cytokines into the vitreous. Similar effects were also detected after 5 weeks of exposure to chronic OHT in an induced glaucoma model. The onset of these immune responses in both spOHT and glaucoma models preceded a 50% deficit in pattern electroretinogram (PERG) amplitude and a significant loss of RGCs 7 days post-injury. The inactivation of inflammasome complexes in Nlrp1−/−, Casp1−/−, and GsdmD−/− knockout animals significantly suppressed the spOHT-induced inflammatory response and protected RGCs. Our results demonstrate that mechanical stress produced by acute repetitive spOHT or chronic OHT is mechanistically linked to inflammasome activation, which leads to RGC dysfunction and death.

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“…TRPV4 channels are calcium-permeable, non-selective cation channels that are susceptible to activation by a variety of stimuli, including mechanical stimuli (e.g., shear stress and stretch), cell metabolites, chemical/pharmacological agents, temperature, changes in pH, hypoxia, as well as cell swelling and osmotic stress among others 9,14,15 . Dysregulated signaling through TRPV4 channels has been linked to a variety of inflammatory diseases, including lung ischemia-reperfusion injury and other lung diseases [16][17][18] , cerebral edema following traumatic brain injury 19 , ocular vascular diseases [20][21][22] , obesity 23,24 , Parkinson's disease 25 , various forms of cardiac dysfunction [26][27][28][29][30] , etc. Importantly, in all these scenarios, aberrant signaling through TRPV4 channels is associated with inflammation and tissue fibrosis, which are key features in the pathophysiology of lymphatic system disease, including lymphedema and lipedema 1,31 .…”

Section: Introductionmentioning

confidence: 99%

“…Dysregulated signaling through TRPV4 channels has been linked to a variety of inflammatory diseases, including lung ischemia-reperfusion injury and other lung diseases 16–18 , cerebral edema following traumatic brain injury 19 , ocular vascular diseases 20–22 , obesity 23,24 , Parkinson’s disease 25 , various forms of cardiac dysfunction 26–30 , etc. Importantly, in all these scenarios, aberrant signaling through TRPV4 channels is associated with inflammation and tissue fibrosis, which are key features in the pathophysiology of lymphatic system disease, including lymphedema and lipedema 1,31 .…”

Section: Introductionmentioning

confidence: 99%

TRPV4-Expressing Tissue-Resident Macrophages Regulate the Function of Collecting Lymphatic Vessels via Thromboxane A2 Receptors in Lymphatic Muscle Cells

Schulz,

Akerstrom,

Song

et al. 2024

Preprint

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Rationale: TRPV4 channels are critical regulators of blood vascular function and have been shown to be dysregulated in many disease conditions in association with inflammation and tissue fibrosis. These are key features in the pathophysiology of lymphatic system diseases, including lymphedema and lipedema; however, the role of TRPV4 channels in the lymphatic system remains largely unexplored. TRPV4 channels are calcium permeable, non-selective cation channels that are activated by diverse stimuli, including shear stress, stretch, temperature, and cell metabolites, which may regulate lymphatic contractile function. Objective: To characterize the expression of TRPV4 channels in collecting lymphatic vessels and to determine the extent to which these channels regulate the contractile function of lymphatics. Methods and Results: Pressure myography on intact, isolated, and cannulated lymphatic vessels showed that pharmacological activation of TRPV4 channels with GSK1016790A (GSK101) led to contractile dysregulation. The response to GSK101 was multiphasic and included, 1) initial robust constriction that was sustained for ≥1 minute and in some instances remained for ≥4 minutes; and 2) subsequent vasodilation and partial or complete inhibition of lymphatic contractions associated with release of nitric oxide. The functional response to activation of TRPV4 channels displayed differences across lymphatics from four anatomical regions, but these differences were consistent across different species (mouse, rat, and non-human primate). Importantly, similar responses were observed following activation of TRPV4 channels in arterioles. The initial and sustained constriction was prevented with the COX inhibitor, indomethacin. We generated a controlled and spatially defined single-cell RNA sequencing (scRNAseq) dataset from intact and microdissected collecting lymphatic vessels. Our data uncovered a subset of macrophages displaying the highest expression of Trpv4 compared to other cell types within and surrounding the lymphatic vessel wall. These macrophages displayed a transcriptomic profile consistent with that of tissue-resident macrophages (TRMs), including differential expression of Lyve1, Cd163, Folr2, Mrc1, Ccl8, Apoe, Cd209f, Cd209d, and Cd209g; and at least half of these macrophages also expressed Timd4. This subset of macrophages also highly expressed Txa2s, which encodes the thromboxane A2 (TXA2) synthase. Inhibition of TXA2 receptors (TXA2Rs) prevented TRPV4-mediated contractile dysregulation. TXA2R activation on LMCs caused an increase in mobilization of calcium from intracellular stores through Ip3 receptors which promoted store operated calcium entry and vasoconstriction. Conclusions: Clinical studies have linked cancer-related lymphedema with an increased infiltration of macrophages. While these macrophages have known anti-inflammatory and pro-lymphangiogenic roles, as well as promote tissue repair, our results point to detrimental effects to the pumping capacity of collecting lymphatic vessels mediated by activation of TRPV4 channels in macrophages. Pharmacological targeting of TRPV4 channels in LYVE1-expressing macrophages or pharmacological targeting of TXA2Rs may offer novel therapeutic strategies to improve lymphatic pumping function and lymph transport in lymphedema.

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TRPV4 channels promote vascular permeability in retinal vascular disease

Cited by 8 publications

References 30 publications

Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes

Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes

The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes

TRPV4-Expressing Tissue-Resident Macrophages Regulate the Function of Collecting Lymphatic Vessels via Thromboxane A2 Receptors in Lymphatic Muscle Cells

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