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

Emma C Tovey Crutchfield; Sarah E Garnish; Jessica Day; Holly Anderton; Shene Chiou; Anne Hempel; Cathrine Hall; Komal M Patel; Pradnya Gangatirkar; Katherine R Martin; Connie S N Li Wai Suen; Alexandra L Garnham; Andrew J Kueh; Ian P Wicks; John Silke; Ueli Nachbur; Andre L Samson; James M Murphy; Joanne M Hildebrand

doi:10.1038/s41418-023-01121-4

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

Cell Death Differ. 2023 Apr;30(4):1059-1071. doi: 10.1038/s41418-023-01121-4. Epub 2023 Feb 8.

Authors

Emma C Tovey Crutchfield^#^{1

2

3}, Sarah E Garnish^#^{1

2}, Jessica Day^{1

2

4}, Holly Anderton^{1

2}, Shene Chiou^{1

2}, Anne Hempel¹, Cathrine Hall¹, Komal M Patel¹, Pradnya Gangatirkar¹, Katherine R Martin^{1

2}, Connie S N Li Wai Suen¹, Alexandra L Garnham¹, Andrew J Kueh^{1

2}, Ian P Wicks^{1

2

4}, John Silke^{1

2}, Ueli Nachbur^{1

2}, Andre L Samson^{1

2}, James M Murphy^{5

6}, Joanne M Hildebrand^{7

8}

Affiliations

¹ The Walter and Eliza Hall Institute, Parkville, VIC, Australia.
² The University of Melbourne, Department of Medical Biology, Parkville, VIC, Australia.
³ The University of Melbourne, Faculty of Medicine, Dentistry and Health Sciences, Parkville, VIC, Australia.
⁴ Royal Melbourne Hospital, Rheumatology Unit, Parkville, VIC, Australia.
⁵ The Walter and Eliza Hall Institute, Parkville, VIC, Australia. jamesm@wehi.edu.au.
⁶ The University of Melbourne, Department of Medical Biology, Parkville, VIC, Australia. jamesm@wehi.edu.au.
⁷ The Walter and Eliza Hall Institute, Parkville, VIC, Australia. jhildebrand@wehi.edu.au.
⁸ The University of Melbourne, Department of Medical Biology, Parkville, VIC, Australia. jhildebrand@wehi.edu.au.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Death
Female
Humans
Infant
Inflammation* / pathology
Mice
Mice, Inbred C57BL
Necrosis / metabolism
Protein Kinases* / metabolism
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
Transcription Factors / metabolism

Substances

Protein Kinases
Transcription Factors
Receptor-Interacting Protein Serine-Threonine Kinases
MLKL protein, human
MLKL protein, mouse