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Signal Transducer and Activator of Transcription 3 (STAT3) Suppresses STAT1/Interferon Signaling Pathway and Inflammation in Senescent Preadipocytes

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submitted on 2024-05-14, 06:12 and posted on 2024-05-14, 06:13 authored by Aisha Y. Madani, Yasser Majeed, Houari B. Abdesselem, Maha V. Agha, Muneera Vakayil, Nour K. Al Sukhun, Najeeb M. Halabi, Pankaj Kumar, Shahina Hayat, Mohamed A. Elrayess, Arash Rafii, Karsten Suhre, Nayef A. Mazloum

Obesity promotes premature aging and dysfunction of white adipose tissue (WAT) through the accumulation of cellular senescence. The senescent cells burden in WAT has been linked to inflammation, insulin-resistance (IR), and type 2 diabetes (T2D). There is limited knowledge about molecular mechanisms that sustain inflammation in obese states. Here, we describe a robust and physiologically relevant in vitro system to trigger senescence in mouse 3T3-L1 preadipocytes. By employing transcriptomics analyses, we discovered up-regulation of key pro-inflammatory molecules and activation of interferon/signal transducer and activator of transcription (STAT)1/3 signaling in senescent preadipocytes, and expression of downstream targets was induced in epididymal WAT of obese mice, and obese human adipose tissue. To test the relevance of STAT1/3 signaling to preadipocyte senescence, we used Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein 9 (CRISPR/Cas9) technology to delete STAT1/3 and discovered that STAT1 promoted growth arrest and cooperated with cyclic Guanosine Monophosphate-Adenosine Monophosphate (GMP-AMP) synthase-stimulator of interferon genes (cGAS-STING) to drive the expression of interferon β (IFNβ), C-X-C motif chemokine ligand 10 (CXCL10), and interferon signaling-related genes. In contrast, we discovered that STAT3 was a negative regulator of STAT1/cGAS-STING signaling—it suppressed senescence and inflammation. These data provide insights into how STAT1/STAT3 signaling coordinates senescence and inflammation through functional interactions with the cGAS/STING pathway.

Other Information

Published in: Antioxidants
License: https://creativecommons.org/licenses/by/4.0/
See article on publisher's website: https://dx.doi.org/10.3390/antiox10020334

History

Language

  • English

Publisher

MDPI

Publication Year

  • 2021

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Hamad Bin Khalifa University
  • College of Health and Life Sciences - HBKU
  • Qatar Biomedical Research Institute - HBKU
  • Neurological Disorders Research Center - QBRI
  • Weill Cornell Medicine - Qatar
  • Hamad Medical Corporation
  • Interim Translational Research Institute - HMC
  • Qatar University
  • Biomedical Research Center - QU

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