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TXNIP links innate host defense mechanisms to oxidative stress and inflammation in retinal Muller glia under chronic hyperglycemia: implications for diabetic retinopathy.

Devi TS, Lee I, Hüttemann M, Kumar A, Nantwi KD, Singh LP - Exp Diabetes Res (2012)

Bottom Line: We also found in vivo that streptozocin-induced diabetic rats have higher retinal TXNIP and innate immune response gene expression than normal rats.Thus, our results show that HG sustains TXNIP up-regulation in Muller glia and evokes a program of cellular defense/survival mechanisms that ultimately lead to oxidative stress, ER stress/inflammation, autophagy and apoptosis.TXNIP is a potential target to ameliorate blinding ocular complications of diabetic retinopathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI 48201, USA.

ABSTRACT
Thioredoxin Interacting Protein (TXNIP) mediates retinal inflammation, gliosis, and apoptosis in experimental diabetes. Here, we investigate the temporal response of Muller glia to high glucose (HG) and TXNIP expression using a rat Muller cell line (rMC1) in culture. We examined if HG-induced TXNIP expression evokes host defense mechanisms in rMC1 in response to metabolic abnormalities. HG causes sustained up-regulation of TXNIP (2 h to 5 days), ROS generation, ATP depletion, ER stress, and inflammation. Various cellular defense mechanisms are activated by HG: (i) NLRP3 inflammasome, (ii) ER stress response (sXBP1), (iii) hypoxic-like HIF-1α induction, (iv) autophagy/mitophagy, and (v) apoptosis. We also found in vivo that streptozocin-induced diabetic rats have higher retinal TXNIP and innate immune response gene expression than normal rats. Knock down of TXNIP by intravitreal siRNA reduces inflammation (IL-1β) and gliosis (GFAP) in the diabetic retina. TXNIP ablation in vitro prevents ROS generation, restores ATP level and autophagic LC3B induction in rMC1. Thus, our results show that HG sustains TXNIP up-regulation in Muller glia and evokes a program of cellular defense/survival mechanisms that ultimately lead to oxidative stress, ER stress/inflammation, autophagy and apoptosis. TXNIP is a potential target to ameliorate blinding ocular complications of diabetic retinopathy.

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Related in: MedlinePlus

A schematic summary of potential cellular responses by retinal Muller glia in chronic hyperglycemia and diabetes. The sequence of molecular events that retinal Muller cells react to chronic hyperglycemia include (i) sustained upregulation of TXNIP, (ii) an initial innate immune and UPR response to excess glucose metabolism and oxidative phosphorylation (ATP generation), (iii) oxidative stress (ROS/RNS generation) and a hypoxia-like response through ATP reduction, (iv) an induction of an autophagic-mitophagic pathway, and (v) ER-stress and inflammation. These cellular responses constitute intrinsic cell survival/defense mechanisms, which, under chronic cell stress and injury, may promote premature cell death and disease progression of DR.
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fig10: A schematic summary of potential cellular responses by retinal Muller glia in chronic hyperglycemia and diabetes. The sequence of molecular events that retinal Muller cells react to chronic hyperglycemia include (i) sustained upregulation of TXNIP, (ii) an initial innate immune and UPR response to excess glucose metabolism and oxidative phosphorylation (ATP generation), (iii) oxidative stress (ROS/RNS generation) and a hypoxia-like response through ATP reduction, (iv) an induction of an autophagic-mitophagic pathway, and (v) ER-stress and inflammation. These cellular responses constitute intrinsic cell survival/defense mechanisms, which, under chronic cell stress and injury, may promote premature cell death and disease progression of DR.

Mentions: In conclusion, we show for the first time that HG sustains TXNIP expression in rat Muller glia and orchestrates a duration-dependent cellular program of innate host defense and survival mechanisms that culminate in oxidative stress, ER stress, autophagy, inflammation, and cell death. While detailed mechanisms are yet to be worked out, a temporal pattern emerges here as to how retinal Muller glia might respond to chronic hyperglycemia in diabetes. These include (i) sustained TXNIP up-regulation, (ii) an initial innate immune and ER stress response to excess glucose metabolism (ATP generation), (iii) oxidative stress and a hypoxia-like response through ATP reduction, (iv) induction of an autophagic-apoptosis pathway, and (v) inflammation. A temporal response of Muller glia to chronic hyperglycemia and potential molecular events are summarized in Figure 10. These findings clearly point to a crucial role of TXNIP in Muller glia activation, oxidative/nitrosative, and ER stress, and sterile inflammation under chronic hyperglycemia and suggest a potential gene and drug target for preventing neurovascular injury/cell death and pathogenesis of DR. Lastly, while our manuscript is in submission, an article came out to demonstrate purinergic and glycemic induction of TXNIP in rMC1 in culture [72], which also supports our findings in the present study.


TXNIP links innate host defense mechanisms to oxidative stress and inflammation in retinal Muller glia under chronic hyperglycemia: implications for diabetic retinopathy.

Devi TS, Lee I, Hüttemann M, Kumar A, Nantwi KD, Singh LP - Exp Diabetes Res (2012)

A schematic summary of potential cellular responses by retinal Muller glia in chronic hyperglycemia and diabetes. The sequence of molecular events that retinal Muller cells react to chronic hyperglycemia include (i) sustained upregulation of TXNIP, (ii) an initial innate immune and UPR response to excess glucose metabolism and oxidative phosphorylation (ATP generation), (iii) oxidative stress (ROS/RNS generation) and a hypoxia-like response through ATP reduction, (iv) an induction of an autophagic-mitophagic pathway, and (v) ER-stress and inflammation. These cellular responses constitute intrinsic cell survival/defense mechanisms, which, under chronic cell stress and injury, may promote premature cell death and disease progression of DR.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3313582&req=5

fig10: A schematic summary of potential cellular responses by retinal Muller glia in chronic hyperglycemia and diabetes. The sequence of molecular events that retinal Muller cells react to chronic hyperglycemia include (i) sustained upregulation of TXNIP, (ii) an initial innate immune and UPR response to excess glucose metabolism and oxidative phosphorylation (ATP generation), (iii) oxidative stress (ROS/RNS generation) and a hypoxia-like response through ATP reduction, (iv) an induction of an autophagic-mitophagic pathway, and (v) ER-stress and inflammation. These cellular responses constitute intrinsic cell survival/defense mechanisms, which, under chronic cell stress and injury, may promote premature cell death and disease progression of DR.
Mentions: In conclusion, we show for the first time that HG sustains TXNIP expression in rat Muller glia and orchestrates a duration-dependent cellular program of innate host defense and survival mechanisms that culminate in oxidative stress, ER stress, autophagy, inflammation, and cell death. While detailed mechanisms are yet to be worked out, a temporal pattern emerges here as to how retinal Muller glia might respond to chronic hyperglycemia in diabetes. These include (i) sustained TXNIP up-regulation, (ii) an initial innate immune and ER stress response to excess glucose metabolism (ATP generation), (iii) oxidative stress and a hypoxia-like response through ATP reduction, (iv) induction of an autophagic-apoptosis pathway, and (v) inflammation. A temporal response of Muller glia to chronic hyperglycemia and potential molecular events are summarized in Figure 10. These findings clearly point to a crucial role of TXNIP in Muller glia activation, oxidative/nitrosative, and ER stress, and sterile inflammation under chronic hyperglycemia and suggest a potential gene and drug target for preventing neurovascular injury/cell death and pathogenesis of DR. Lastly, while our manuscript is in submission, an article came out to demonstrate purinergic and glycemic induction of TXNIP in rMC1 in culture [72], which also supports our findings in the present study.

Bottom Line: We also found in vivo that streptozocin-induced diabetic rats have higher retinal TXNIP and innate immune response gene expression than normal rats.Thus, our results show that HG sustains TXNIP up-regulation in Muller glia and evokes a program of cellular defense/survival mechanisms that ultimately lead to oxidative stress, ER stress/inflammation, autophagy and apoptosis.TXNIP is a potential target to ameliorate blinding ocular complications of diabetic retinopathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI 48201, USA.

ABSTRACT
Thioredoxin Interacting Protein (TXNIP) mediates retinal inflammation, gliosis, and apoptosis in experimental diabetes. Here, we investigate the temporal response of Muller glia to high glucose (HG) and TXNIP expression using a rat Muller cell line (rMC1) in culture. We examined if HG-induced TXNIP expression evokes host defense mechanisms in rMC1 in response to metabolic abnormalities. HG causes sustained up-regulation of TXNIP (2 h to 5 days), ROS generation, ATP depletion, ER stress, and inflammation. Various cellular defense mechanisms are activated by HG: (i) NLRP3 inflammasome, (ii) ER stress response (sXBP1), (iii) hypoxic-like HIF-1α induction, (iv) autophagy/mitophagy, and (v) apoptosis. We also found in vivo that streptozocin-induced diabetic rats have higher retinal TXNIP and innate immune response gene expression than normal rats. Knock down of TXNIP by intravitreal siRNA reduces inflammation (IL-1β) and gliosis (GFAP) in the diabetic retina. TXNIP ablation in vitro prevents ROS generation, restores ATP level and autophagic LC3B induction in rMC1. Thus, our results show that HG sustains TXNIP up-regulation in Muller glia and evokes a program of cellular defense/survival mechanisms that ultimately lead to oxidative stress, ER stress/inflammation, autophagy and apoptosis. TXNIP is a potential target to ameliorate blinding ocular complications of diabetic retinopathy.

Show MeSH
Related in: MedlinePlus