Dataset Information

NLRP3 Inflammasome Priming in the Retina of Diabetic Mice Requires REDD1-Dependent Activation of GSK3β.

ABSTRACT:

Purpose

Inflammasome activation has been implicated in the development of retinal complications caused by diabetes. This study was designed to identify signaling events that promote retinal NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in response to diabetes.

Methods

Diabetes was induced in mice by streptozotocin administration. Retinas were examined after 16 weeks of diabetes. Human MIO-M1 Müller cells were exposed to hyperglycemic culture conditions. Genetic and pharmacological interventions were used to interrogate signaling pathways. Visual function was assessed in mice using a virtual optomotor system.

Results

In the retina of diabetic mice and in Müller cell cultures, NLRP3 and interleukin-1β (IL-1β) were increased in response to hyperglycemic conditions and the stress response protein Regulated in Development and DNA damage 1 (REDD1) was required for the effect. REDD1 deletion prevented caspase-1 activation in Müller cells exposed to hyperglycemic conditions and reduced IL-1β release. REDD1 promoted nuclear factor κB signaling in cells exposed to hyperglycemic conditions, which was necessary for an increase in NLRP3. Expression of a constitutively active GSK3β variant restored NLRP3 expression in REDD1-deficient cells exposed to hyperglycemic conditions. GSK3 activity was necessary for increased NLRP3 expression in the retina of diabetic mice and in cells exposed to hyperglycemic conditions. Müller glia-specific REDD1 deletion prevented increased retinal NLRP3 levels and deficits in contrast sensitivity in diabetic mice.

Conclusions

The data support a role for REDD1-dependent activation of GSK3β in NLRP3 inflammasome transcriptional priming and in the production of IL-1β by Müller glia in response to diabetes.

SUBMITTER: McCurry CM

PROVIDER: S-EPMC10981446 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Publications

NLRP3 Inflammasome Priming in the Retina of Diabetic Mice Requires REDD1-Dependent Activation of GSK3β.

McCurry Christopher M CM Sunilkumar Siddharth S Subrahmanian Sandeep M SM Yerlikaya Esma I EI Toro Allyson L AL VanCleave Ashley M AM Stevens Shaunaci A SA Barber Alistair J AJ Sundstrom Jeffery M JM Dennis Michael D MD

Investigative ophthalmology & visual science 20240301 3

<h4>Purpose</h4>Inflammasome activation has been implicated in the development of retinal complications caused by diabetes. This study was designed to identify signaling events that promote retinal NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in response to diabetes.<h4>Methods</h4>Diabetes was induced in mice by streptozotocin administration. Retinas were examined after 16 weeks of diabetes. Human MIO-M1 Müller cells were exposed to hyperglycemic culture con ...[more]

PMID: 38546584

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Dataset Information

NLRP3 Inflammasome Priming in the Retina of Diabetic Mice Requires REDD1-Dependent Activation of GSK3β.

Purpose

Methods

Results

Conclusions

Publications

NLRP3 Inflammasome Priming in the Retina of Diabetic Mice Requires REDD1-Dependent Activation of GSK3β.

Similar Datasets

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