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MLKL deficiency protects against low-grade, sterile inflammation in aged mice
Emma C Tovey Crutchfield1,2,3, Sarah E Garnish1,2, Jessica Day1,2,4
1The Walter and Eliza Hall Institute, Parkville, VIC, Australia.
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.
Insights
Genetic deletion of MLKL in female mice delays immune system aging and reduces chronic sterile inflammation. This suggests MLKL plays a role in aging-related inflammation and could be a target for therapies.
Area of Science:
- Immunology
- Cell Biology
- Aging Research
Background:
- Necroptosis, mediated by MLKL and RIPK3, is an inflammatory cell death pathway implicated in disease.
- Emerging evidence suggests a role for necroptosis in the aging process.
- Understanding necroptosis's impact on aging is crucial for developing age-related disease interventions.
Purpose of the Study:
- To conduct a comprehensive analysis of age-related histopathological and immunological changes in mice lacking MLKL or RIPK3.
- To investigate the specific role of MLKL in age-associated immune system decline and chronic inflammation.
Main Methods:
- Analysis of Mlkl-/- and Ripk3-/- mice on a C57BL/6J genetic background.
- Assessment of age-related histopathological and immunological phenotypes in 17-month-old mice.
- Comparison of immune cell infiltrates and myocyte regeneration in knockout versus wild-type littermate controls.
Main Results:
- Genetic deletion of MLKL in female mice interrupted immune system aging, delaying the reduction of circulating lymphocytes.
- Mlkl-/- female mice showed protection against age-related chronic sterile inflammation in connective tissue and skeletal muscle.
- Reduced immune cell infiltration and fewer regenerating myocytes were observed in Mlkl-/- female mice compared to controls.
Conclusions:
- MLKL is implicated in age-related sterile inflammation, highlighting its role in the aging process.
- Targeting MLKL may offer a therapeutic strategy for mitigating age-associated inflammation.
- These findings suggest potential applications for long-term anti-necroptotic therapies in human aging.
