Necroptosis induced by MLKL overexpression in liver triggers cellular senescence and leads to chronic inflammation and fibrosis.

Ramasamy Selvarani, Sunho Lee, Mani Saminathan, Puvarajan Boovalingam, Kavitha Kurup, Kevin Pham, Roman F Wolf, Willard M Freeman, Archana Unnikrishnan, Arlan Richardson

Biochemistry & Physiology, University of Oklahoma Health Sciences, Oklahoma City, OK, USA.Biochemistry & Physiology, University of Oklahoma Health Sciences, Oklahoma City, OK, USA. · pubmed

Paper

Abstract

Cellular senescence and necroptosis are two cell fates, which trigger an inflammatory response and increase with age, that have been proposed to play a role in inflammaging. In this study, we performed the first study to directly test the possible interaction between necroptosis and cellular senescence. Using a novel Mlkl-KI mouse model, we were able to specifically induce (~ 4-fold) the overexpression of MLKL, the necroptotic executioner, in hepatocytes (hMlkl-KI mice). The overexpression of MLKL led to increased necroptosis and cell damage/death in liver, as shown by increased levels of MLKL-oligomers, TUNEL staining, and Ki-67 staining in the livers, as well as increased ALT activity and HMGB1 levels in the plasma. The increase in necroptosis was paralleled by an increase in cellular senescence. We observed increased levels of p16

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Research summary

The paper claims that MLKL overexpression in liver cells induces necroptosis, leading to cellular senescence and chronic inflammation. This research is relevant as it explores the mechanisms linking necroptosis and cellular senescence, which are both implicated in the aging process and age-related diseases, potentially addressing root causes of aging.

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