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

Tovey Crutchfield, EC; Garnish, SE; Day, J; Anderton, H; Chiou, S; Hempel, A; Hall, C; Patel, KM; Gangatirkar, P; Martin, KR; Li Wai Suen, CSN; Garnham, AL; Kueh, AJ; Wicks, IP; Silke, J; Nachbur, U; Samson, AL; Murphy, JM; Hildebrand, JM

Author(s): Tovey Crutchfield, EC; Garnish, SE; Day, J; Anderton, H; Chiou, S; Hempel, A; Hall, C; Patel, KM; Gangatirkar, P; Martin, KR; Li Wai Suen, CSN; Garnham, AL; Kueh, AJ; Wicks, IP; Silke, J; Nachbur, U; Samson, AL; Murphy, JM; Hildebrand, JM;
Details: Publication Year 2023-02-08,Volume 30,Issue #4,Page 1059-1071
Journal Title: Cell Death & Differentiation
Abstract: 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.
Publisher: NPG
Research Division(s): Inflammation; Bioinformatics; Ubiquitin Signalling; Blood Cells And Blood Cancer
PubMed ID: 36755069
Publisher's Version: https://doi.org/10.1038/s41418-023-01121-4
Open Access at Publisher's Site: https://doi.org/10.1038/s41418-023-01121-4
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: s41418-023-01121-4.pdf - (6.16MB, application/pdf)

Creation Date: 2023-03-17 11:09:18

Last Modified: 2023-04-12 09:44:17