TNF-alpha driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging
Open Access
- 28 August 2019
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 134 (9), 727-740
- https://doi.org/10.1182/blood.2019000200
Abstract
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 alpha (TNF-alpha) as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. We further showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF-alpha 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-alpha was endogenously increased) and from young mice exposed to exogenous TNF-alpha exhibited significant mitochondria! changes characterized by elevated mitochondria! mass and increased oxygen consumption during activation. These mitochondria! changes were mitigated upon TNF-alpha blockade. Similar increases in platelet mitochondria! mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF-alpha 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-alpha critically regulates megakaryocytes resident in the bone marrow niche and aging-associated platelet hyperreactivity and thrombosis.Keywords
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