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

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 necrop...

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Published inbioRxiv
Main Authors Tovey, Emma C, Garnish, Sarah E, Day, Jessica, Anderton, Holly, Chiou, Shene, Hempel, Anne, Hall, Cathrine, Patel, Komal, Gangatirkar, Pradnya, Connie Sn Li Wai Suen, Garnham, Alexandra, Kueh, Andrew J, Nachbur, Ueli, Samson, Andre L, Murphy, James M, Hildebrand, Joanne M
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Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 17.10.2022
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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/6J genetic background. We show that genetic deletion of Mlkl, but not Ripk3, in female mice interrupts immune system aging, specifically delaying the age-related reduction of circulating lymphocytes. Mlkl-/- female mice were also protected against age-related, low-grade chronic sterile inflammation, with a reduced number of inflammatory infiltrates present in the connective and muscle tissue at 17 months relative to wild-type littermates. These observations implicate MLKL in age-related sterile inflammation, suggesting a possible application for long-term anti-necroptotic therapy in humans. Competing Interest Statement S.E.G., A.H., K.M.P., P.G., U.N., A.L.S., J.M.M. and J.M.H. contribute to or have contributed to project developing necroptosis inhibitors in collaboration with Anaxis Pharma. The other authors declare no competing interests.
AbstractList 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/6J genetic background. We show that genetic deletion of Mlkl, but not Ripk3, in female mice interrupts immune system aging, specifically delaying the age-related reduction of circulating lymphocytes. Mlkl-/- female mice were also protected against age-related, low-grade chronic sterile inflammation, with a reduced number of inflammatory infiltrates present in the connective and muscle tissue at 17 months relative to wild-type littermates. These observations implicate MLKL in age-related sterile inflammation, suggesting a possible application for long-term anti-necroptotic therapy in humans. Competing Interest Statement S.E.G., A.H., K.M.P., P.G., U.N., A.L.S., J.M.M. and J.M.H. contribute to or have contributed to project developing necroptosis inhibitors in collaboration with Anaxis Pharma. The other authors declare no competing interests.
Author Hall, Cathrine
Chiou, Shene
Anderton, Holly
Kueh, Andrew J
Patel, Komal
Garnham, Alexandra
Hempel, Anne
Samson, Andre L
Garnish, Sarah E
Nachbur, Ueli
Hildebrand, Joanne M
Tovey, Emma C
Gangatirkar, Pradnya
Murphy, James M
Connie Sn Li Wai Suen
Day, Jessica
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SubjectTerms Aging
Cell death
Immune system
Inflammation
Lymphocytes
Necroptosis
Phenotypes
Title MLKL deficiency protects against low-grade, sterile inflammation in aged mice
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