TY - JOUR
T1 - MLKL deficiency protects against low-grade, sterile inflammation in aged mice
AU - Tovey Crutchfield, Emma C.
AU - Garnish, Sarah E.
AU - Day, Jessica
AU - Anderton, Holly
AU - Chiou, Shene
AU - Hempel, Anne
AU - Hall, Cathrine
AU - Patel, Komal M.
AU - Gangatirkar, Pradnya
AU - Martin, Katherine R.
AU - Li Wai Suen, Connie S.N.
AU - Garnham, Alexandra L.
AU - Kueh, Andrew J.
AU - Wicks, Ian P.
AU - Silke, John
AU - Nachbur, Ueli
AU - Samson, Andre L.
AU - Murphy, James M.
AU - Hildebrand, Joanne M.
N1 - Funding Information:
We thank the following people for their technical assistance with the experiments completed in this manuscript; Aira Nuguid and Tina Cardamone (Phenomics Australia Histopathology and Slide Scanning Service - The University of Melbourne), WEHI Bioservices, WEHI Histology Center and WEHI Cytometry Facility. The generation of the Ripk3-/-mice used in this study was supported by Phenomics Australia and the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. We thank Cynthia Louis and Najoua Lalaoui for the provision of important resources, and Kate Lawlor for helpful discussions.
Funding Information:
We thank the following people for their technical assistance with the experiments completed in this manuscript; Aira Nuguid and Tina Cardamone (Phenomics Australia Histopathology and Slide Scanning Service - The University of Melbourne), WEHI Bioservices, WEHI Histology Center and WEHI Cytometry Facility. The generation of the Ripk3 mice used in this study was supported by Phenomics Australia and the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. We thank Cynthia Louis and Najoua Lalaoui for the provision of important resources, and Kate Lawlor for helpful discussions. -/-
Funding Information:
We are grateful to the National Health and Medical Research Council for fellowship (IPW, 1154325; JS, 1195038; JMM, 1172929; JMH, 1142669), grant (IPW, 1113577; ALS, 2002965; JMH, 2011584) and infrastructure (IRIISS 9000719) support; Anaxis Pharma Pty Ltd for funding support; and the Victorian State Government Operational Infrastructure Support scheme. JD is supported by project grants from the Sylvia and Charles Viertel Charitable Foundation and Royal Australian College of Physicians. KRM was supported by an Arthritis Australia project grant. JD and IPW gratefully acknowledge the support of the Reid Charitable Trusts. We also acknowledge scholarship support for SEG (Australian Government Research Training Program Stipend Scholarship, Wendy Dowsett Scholarship), SC (WEHI Handman PhD Scholarship) and ECTC (Attracting and Retaining Clinician-Scientists’ Scholarship).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/4
Y1 - 2023/4
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85147704971
U2 - 10.1038/s41418-023-01121-4
DO - 10.1038/s41418-023-01121-4
M3 - Article
C2 - 36755069
AN - SCOPUS:85147704971
SN - 1350-9047
VL - 30
SP - 1059
EP - 1071
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 4
ER -
SDG 3 Good Health and Well-being