TXNRD1 Drives the Innate Immune Response in Senescent Cells With Implications for Age-Associated Inflammation

Authors

Xue Hao
Bo Zhao
Martina Towers
Liping Liao
Edgar Luzete Monteiro
Xin Xu
Christina Freeman
Hongzhuang Peng
Hsin-Yao Tang
Aaron Havas
Andrew V Kossenkov
Shelley L Berger
Peter D Adams
David W Speicher
David Schultz
Ronen Marmorstein
Kenneth S Zaret
Rugang Zhang

Publication Date

2-1-2024

Journal

Nature Aging

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.

Keywords

Animals, Mice, Cellular Senescence, Immunity, Innate, Inflammation, Nucleotidyltransferases, Signal Transduction, Thioredoxin Reductase 1

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Associated Data

PMID: 38267705