2. Academic Validation
  3. TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation

TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation

  • Nat Aging. 2024 Jan 24. doi: 10.1038/s43587-023-00564-1.
Xue Hao 1,  Bo Zhao 1 2,  Martina Towers 1,  Liping Liao 1,  Edgar Luzete Monteiro 3,  Xin Xu 4,  Christina Freeman 5,  Hongzhuang Peng 5,  Hsin-Yao Tang 6,  Aaron Havas 7,  Andrew V Kossenkov 8,  Shelley L Berger 3,  Peter D Adams 7,  David W Speicher 6,  David Schultz 5,  Ronen Marmorstein 4,  Kenneth S Zaret 3,  Rugang Zhang 9 10
Affiliations

Affiliations

  • 1 Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2 Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • 3 Penn Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 4 Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 5 High-throughput Screening Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 6 Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.
  • 7 Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA, USA.
  • 8 Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, USA.
  • 9 Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
  • 10 Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA. [email protected].
PMID: 38267705 DOI: 10.1038/s43587-023-00564-1
Abstract

Sterile inflammation, also known as 'inflammaging', is a hallmark of tissue aging. Cellular senescence contributes to tissue aging, in part, through the secretion of proinflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). The genetic variability of thioredoxin reductase 1 (TXNRD1) is associated with aging and age-associated phenotypes such as late-life survival, activity of daily living and physical performance in old age. TXNRD1's role in regulating tissue aging has been attributed to its enzymatic role in cellular redox regulation. Here, we show that TXNRD1 drives the SASP and inflammaging through the Cyclic GMP-AMP Synthase (cGAS)-stimulator of interferon genes (STING) innate immune response pathway independently of its enzymatic activity. TXNRD1 localizes to cytoplasmic chromatin fragments and interacts with cGAS in a senescence-status-dependent manner, which is necessary for the SASP. TXNRD1 enhances the enzymatic activity of cGAS. TXNRD1 is required for both the tumor-promoting and immune surveillance functions of senescent cells, which are mediated by the SASP in vivo in mouse models. Treatment of aged mice with a TXNRD1 inhibitor that disrupts its interaction with cGAS, but not with an inhibitor of its enzymatic activity alone, downregulated markers of inflammaging in several tissues. In summary, our results show that TXNRD1 promotes the SASP through the innate immune response, with implications for inflammaging. This suggests that the TXNRD1-cGAS interaction is a relevant target for selectively suppressing inflammaging.

Figures
Products