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

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 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.

COVID-19 infection results in alterations of the kynurenine pathway and fatty acid metabolism that correlate with IL-6 levels and renal status

“…In this context, clinical trials are currently underway to determine the impact of anticoagulants (e.g., heparin) or pro-fibrinolytic drugs (e.g., tissue plasminogen activator) in ameliorating severe COVID-19 infection with thromboembolic complications (21). Interestingly, platelets from older subjects are hypercoagulable in the presence of pro-inflammatory stimuli (22), which may help explain the increased mortality rates in older COVID-19 patients. Of note, small molecule metabolites are relevant in treating coagulopathies (e.g., tranexamic acid to treat hyperfibrinolysis in actively bleeding patients) (23).…”

Comparative Proteomic Analyses of the Liver in D‐Galactosamine‐Sensitized Mice Treated with Different Toll‐Like Receptor Agonists

“…[ 21 ] A recent study also reported the platelet hyperreactivity of aging through TNF‐α‐driven inflammation and mitochondrial dysfunction in mice. [ 22 ] These results suggest an interaction of platelet and TNF‐α in D‐GalN sensitized ALF mice. However, how these processes affect rapid development of ALF which requires further extensive studies.…”

Platelet activation in experimental murine neonatal pulmonary hypertension

“…Flow cytometry data were analyzed using Kaluza flow analysis software (Beckman Coulter) and Flowjo (Flowjo, LLC). Gating strategy as previously described (Davizon‐Castillo et al, 2019 ).…”