MLKL deficiency protects against low-grade, sterile inflammation in aged mice
Tovey, E. C.; Garnish, S. E.; Day, J.; Anderton, H.; Chiou, S.; Hempel, A.; Hall, C.; Patel, K.; Gangatirkar, P.; Li Wai Suen, C. S. N.; Garnham, A.; Kueh, A. J.; Nachbur, U.; Samson, A. L.; Murphy, J. M.; Hildebrand, J. M.
Show 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.
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