Necroptosis increases with age in the brain and contributes to age-related neuroinflammation

• Published in: GeroScience Vol. 43; no. 5; pp. 2345 - 2361
• Main Authors: Thadathil, Nidheesh, Nicklas, Evan H., Mohammed, Sabira, Lewis, Tommy L., Richardson, Arlan, Deepa, Sathyaseelan S.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.10.2021; Springer Nature B.V
• Subjects: Age; Aging; Animals; Astrocytes; Biomedical and Life Sciences; Brain; Brain - metabolism; Cell Biology; Cell death; Central nervous system; Cognitive ability; Geriatrics/Gerontology; Glial fibrillary acidic protein; Hippocampus; IL-1β; Immunoreactivity; Inflammation; Interleukin 6; Life Sciences; Mice; Microglia; Molecular Medicine; Necroptosis; Neuroinflammatory Diseases; Original; Original Article; Protein Kinases - metabolism; Aging; Brain; Neuroinflammation; Necrostatin-1s; Necroptosis
• ISSN: 2509-2715; 2509-2723
• DOI: 10.1007/s11357-021-00448-5

Chronic inflammation of the central nervous system (CNS), termed neuroinflammation, is a hallmark of aging and a proposed mediator of cognitive decline associated with aging. Neuroinflammation is characterized by the persistent activation of microglia, the innate immune cells of the CNS, with damage-associated molecular patterns (DAMPs) being one of the well-known activators of microglia. Because necroptosis is a cell death pathway that induces inflammation through the release of DAMPs, we hypothesized that an age-associated increase in necroptosis contributes to increased neuroinflammation with age. The marker of necroptosis, phosphorylated form of MLKL (P-MLKL), and kinases in the necroptosis pathway (RIPK1, RIPK3, and MLKL) showed a region-specific increase in the brain with age, specifically in the cortex layer V and the CA3 region of the hippocampus of mice. Similarly, MLKL-oligomers, which cause membrane binding and permeabilization, were significantly increased in the cortex and hippocampus of old mice relative to young mice. Nearly 70 to 80% of P-MLKL immunoreactivity was localized to neurons and less than 10% was localized to microglia, whereas no P-MLKL was detected in astrocytes. P-MLKL expression in neurons was detected in the soma, not in the processes. Blocking necroptosis using Mlkl −/− mice reduced markers of neuroinflammation (Iba-1 and GFAP) in the brains of old mice, and short-term treatment with the necroptosis inhibitor, necrostatin-1s, reduced expression of proinflammatory cytokines, IL-6 and IL-1β, in the hippocampus of old mice. Thus, our data demonstrate for the first time that brain necroptosis increases with age and contributes to age-related neuroinflammation in mice.