MLKL deficiency protects against low-grade, sterile inflammation in aged mice

• Published in: Cell death and differentiation Vol. 30; no. 4; pp. 1059 - 1071
• Main Authors: Tovey Crutchfield, Emma C., Garnish, Sarah E., Day, Jessica, Anderton, Holly, Chiou, Shene, Hempel, Anne, Hall, Cathrine, Patel, Komal M., Gangatirkar, Pradnya, Martin, Katherine R., Li Wai Suen, Connie S. N., Garnham, Alexandra L., Kueh, Andrew J., Wicks, Ian P., Silke, John, Nachbur, Ueli, Samson, Andre L., Murphy, James M., Hildebrand, Joanne M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2023; Nature Publishing Group
• Subjects: 13/95; 14/63; 59; 631/443/7; 631/45/275; 64/60; 82/80; 96; 96/106; 96/2; Aging; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell Death; Connective tissues; Female; Humans; Immune system; Infant; Inflammation; Inflammation - pathology; Life Sciences; Lymphocytes; Mice; Mice, Inbred C57BL; Myocytes; Necroptosis; Necrosis - metabolism; Phenotypes; Protein Kinases - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Skeletal muscle; Stem Cells; Transcription Factors - metabolism
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-023-01121-4

MLKL and RIPK3 are the core signaling proteins of the inflammatory cell death pathway, necroptosis, which is a known mediator and modifier of human disease. Necroptosis has been implicated in the progression of disease in almost every physiological system and recent reports suggest a role for necroptosis in aging. Here, we present the first comprehensive analysis of age-related histopathological and immunological phenotypes in a cohort of Mlkl –/– and Ripk3 –/– mice on a congenic C57BL/6 J genetic background. We show that genetic deletion of Mlkl in female mice interrupts immune system aging, specifically delaying the age-related reduction of circulating lymphocytes. -Seventeen-month-old Mlkl –/– female mice were also protected against age-related chronic sterile inflammation in connective tissue and skeletal muscle relative to wild-type littermate controls, exhibiting a reduced number of immune cell infiltrates in these sites and fewer regenerating myocytes. These observations implicate MLKL in age-related sterile inflammation, suggesting a possible application for long-term anti-necroptotic therapy in humans.