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Experimental Type 2 diabetes and lipotoxicity-associated neuroinflammation involve mitochondrial DNA-mediated cGAS/STING axis: implication of Type-1 interferon response in cognitive impairment

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Abstract

Type-1 IFN (interferon)-associated innate immune response is increasingly getting attention in neurodegenerative and metabolic diseases like type 2 diabetes (T2DM). However, its significance in T2DM/lipotoxicity-induced neuroglia changes and cognitive impairment is missing. The present study aims to evaluate the involvement of cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon gene), IRF3 (interferon regulatory factor-3), TBK (TANK binding kinase)-mediated Type-1 IFN response in the diabetic brain, and lipotoxicity (palmitate-bovine serum albumin conjugate/PA-BSA)-induced changes in cells (neuro2a and BV2). T2DM was induced in C57/BL6 mice by feeding on a high-fat diet (HFD, 60% Kcal) for 16 weeks and injecting a single dose of streptozotocin (100 mg/kg, i.p) in the 12th week. Plasma biochemical parameter analysis, neurobehavioral assessment, protein expression, and quantitative polymerase chain reaction study were carried out to decipher the hypothesis. T2DM-associated metabolic and lipotoxic stress led to mitochondrial impairment causing leakage of mtDNA to the cytoplasm further commencing cGAS activation and its downstream signaling. The diseased hippocampus and cortex showed decreased expression of synaptophysin (p < 0.01) and PSD-95 (p < 0.01, p < 0.05) with increased expression of cGAS (p < 0.001), p-STING (p < 0.001), p-STAT1 (signal transducer and activator of transcription) (p < 0.01), and IFN-β (p < 0.001) compared to normal control. The IFN-β/p-STAT1-mediated microglia activation was executed employing a conditioned media approach. C-176, a selective STING inhibitor, alleviated cGAS/p-STING/IFN-β expression and proinflammatory microglia/M1-associated markers (CD16 expression, CXCL10, TNF-α, IL-1β mRNA fold change) in the diabetic brain. The present study suggests Type-1IFN response may result in neuroglia dyshomeostasis affecting normal brain function. Alleviating STING signaling has the potential to protect T2DM-associated central ailment.

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Data availability

The data which supports this study is available on request from the corresponding author upon appropriate request.

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Acknowledgements

The authors would like to acknowledge the financial support provided by the Department of Pharmacology and Toxicology, NIPER Hyderabad, and the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India, for carrying out this work.

Funding

This work is supported by the National Institute of Pharmaceutical Education and Research, Hyderabad, and the Department of Pharmaceuticals, Ministry of Chemical and Fertilizers, Govt. of India.

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  1. Molecular & Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India

    Kumari Preeti, Anika Sood, Valencia Fernandes, Islauddin Khan, Dharmendra Kumar Khatri & Shashi Bala Singh

  2. Department of Pharmacology, Shobhaben Pratapbai Patel School of Pharmacy & Technology Management, SVKM’s Narsee Monjee Institute of Management Studies (NMIMS) Deemed-to-University, Mumbai, 400056, India

    Dharmendra Kumar Khatri

  3. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India

    Shashi Bala Singh

Authors
  1. Kumari Preeti
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  2. Anika Sood
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  3. Valencia Fernandes
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  4. Islauddin Khan
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  5. Dharmendra Kumar Khatri
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  6. Shashi Bala Singh
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Contributions

All authors take responsibility for the integrity and accuracy of this manuscript. KP, DKK, and SBS contributed to the conceptualization, designing, and seamless execution of the research; KP performed studies, evaluated data, and wrote the manuscript; AS, VF, and IK performed studies, evaluated data, and reviewed the manuscript; DKK and SBS reviewed, edited the manuscript, and supervised the research work.

Corresponding authors

Correspondence to Dharmendra Kumar Khatri or Shashi Bala Singh.

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Ethics approval

This present study was conducted under the regulation of the Committee for Control and Supervision of Experiments on Animals (CCSEA) and Institutional Animal Ethical Committee (IAEC)-NIPER-Hyderabad Telangana, India, and according to Animal Research Reporting of In Vivo Experiments (ARRIVE) guidelines [50] after getting approval of protocol no NIP/10/2019/PC/343 and NIP/05/2020/PC/385.

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The authors declare no competing interests.

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Preeti, K., Sood, A., Fernandes, V. et al. Experimental Type 2 diabetes and lipotoxicity-associated neuroinflammation involve mitochondrial DNA-mediated cGAS/STING axis: implication of Type-1 interferon response in cognitive impairment. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-03933-y

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