TNF-α-driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging.
In: Blood, Jg. 134 (2019-08-29), Heft 9, S. 727
academicJournal
Zugriff:
Aging and chronic inflammation are independent risk factors for the development of atherothrombosis and cardiovascular disease. We hypothesized that aging-associated inflammation promotes the development of platelet hyperreactivity and increases thrombotic risk during aging. Functional platelet studies in aged-frail adults and old mice demonstrated that their platelets are hyperreactive and form larger thrombi. We identified tumor necrosis factor α (TNF-α) as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. We further showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF-α receptors in vivo in a mouse model of aging. Analysis of the bone marrow compartments showed significant platelet-biased hematopoiesis in old mice reflected by increased megakaryocyte-committed progenitor cells, megakaryocyte ploidy status, and thrombocytosis. Single-cell RNA-sequencing analysis of native mouse megakaryocytes showed significant reprogramming of inflammatory, metabolic, and mitochondrial gene pathways in old mice that appeared to play a significant role in determining platelet hyperreactivity. Platelets from old mice (where TNF-α was endogenously increased) and from young mice exposed to exogenous TNF-α exhibited significant mitochondrial changes characterized by elevated mitochondrial mass and increased oxygen consumption during activation. These mitochondrial changes were mitigated upon TNF-α blockade. Similar increases in platelet mitochondrial mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF-α levels are also increased. Furthermore, metabolomics studies of platelets from young and old mice demonstrated age-dependent metabolic profiles that may differentially poise platelets for activation. Altogether, we present previously unrecognized evidence that TNF-α critically regulates megakaryocytes resident in the bone marrow niche and aging-associated platelet hyperreactivity and thrombosis.
(© 2019 by The American Society of Hematology.)
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TNF-α-driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging.
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Autor/in / Beteiligte Person: | Davizon-Castillo, P ; McMahon, B ; Aguila, S ; Bark, D ; Ashworth, K ; Allawzi, A ; Campbell, RA ; Montenont, E ; Nemkov, T ; D'Alessandro, A ; Clendenen, N ; Shih, L ; Sanders, NA ; Higa, K ; Cox, A ; Padilla-Romo, Z ; Hernandez, G ; Wartchow, E ; Trahan, GD ; Nozik-Grayck, E ; Jones, K ; Pietras, EM ; DeGregori, J ; Rondina, MT ; Di Paola, J |
Zeitschrift: | Blood, Jg. 134 (2019-08-29), Heft 9, S. 727 |
Veröffentlichung: | 2021- : [New York] : Elsevier ; <i>Original Publication</i>: New York, Grune & Stratton [etc.], 2019 |
Medientyp: | academicJournal |
ISSN: | 1528-0020 (electronic) |
DOI: | 10.1182/blood.2019000200 |
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