TNF-α–driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging

• Published in: Blood 2019-08, Vol.134 (9), p.727-740
• Main Authors: Davizon-Castillo, Pavel, McMahon, Brandon, Aguila, Sonia, Bark, David, Ashworth, Katrina, Allawzi, Ayed, Campbell, Robert A., Montenont, Emilie, Nemkov, Travis, D’Alessandro, Angelo, Clendenen, Nathan, Shih, Lauren, Sanders, Natalie A., Higa, Kelly, Cox, Allaura, Padilla-Romo, Zavelia, Hernandez, Giovanni, Wartchow, Eric, Trahan, George D., Nozik-Grayck, Eva, Jones, Kenneth, Pietras, Eric M., DeGregori, James, Rondina, Matthew T., Di Paola, Jorge
• Format: Article
• Language: English
• Subjects: Aging; Animals; Blood Platelets - immunology; Blood Platelets - pathology; Inflammation - immunology; Inflammation - pathology; Megakaryocytes - immunology; Megakaryocytes - pathology; Mice; Mice, Inbred C57BL; Mitochondria - immunology; Mitochondria - pathology; Platelet Activation; Plenary Paper; Thrombosis - immunology; Thrombosis - pathology; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2019000200

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. •Aging-associated inflammation by TNF-α plays an important role in the development of platelet hyperreactivity during aging.•Aging-associated platelet hyperreactivity is associated with megakaryocytic inflammatory, metabolic, and mitochondrial reprogramming. [Display omitted]