TY - JOUR
T1 - TNF-a–driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging
AU - Davizon-Castillo, Pavel
AU - McMahon, Brandon
AU - Aguila, Sonia
AU - Bark, David
AU - Ashworth, Katrina
AU - Allawzi, Ayed
AU - Campbell, Robert A.
AU - Montenont, Emilie
AU - Nemkov, Travis
AU - D’Alessandro, Angelo
AU - Clendenen, Nathan
AU - Shih, Lauren
AU - Sanders, Natalie A.
AU - Higa, Kelly
AU - Cox, Allaura
AU - Padilla-Romo, Zavelia
AU - Hernandez, Giovanni
AU - Wartchow, Eric
AU - Trahan, George D.
AU - Nozik-Grayck, Eva
AU - Jones, Kenneth
AU - Pietras, Eric M.
AU - DeGregori, James
AU - Rondina, Matthew T.
AU - Paola, Jorge Di
N1 - Funding Information:
This work was supported by: the Pediatric Scientist Development Program of the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development, grant K12HD00050 (P.D.-C.); the 2018 American Society of Hematology Research Training Award for Fellows (P.D.-C.); National Heart, Lung, and Blood Institute grants R01HL120728 (J.D.P.), HL142804 (M.T.R.), HL112311, and HL126547; grant H30MC24049 of the Mountain States Hemophilia Network (J.D.P.); the Postle Chair of Pediatric Cancer and Blood Disorders (J.D.P.); National Cancer Institute grants R01CA180175 (J.D.) and F30CA210383-01 (K.H.); National Institute on Aging grant AG04802 (M.T.R.); National Heart, Lung, and Blood Institute grants 1R35HL139726-01 (E.N.-G.) and T32 HL007171 (A.A.); and American Heart Association grant 19POST34380396 (A.A.). Additional support was received by the National Center for Research Resources of the National Institutes of Health under award number 1S10RR026802-01, the Flow Cytometry Core at the University of Utah, and the Cancer Center Shared Resources at the University of Colorado (National Cancer Institute grant 2-P30-CA46934).
Publisher Copyright:
© 2019 by The American Society of Hematology
PY - 2019/8/29
Y1 - 2019/8/29
N2 - 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 a (TNF-a) as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. We further showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF-a 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-a was endogenously increased) and from young mice exposed to exogenous TNF-a exhibited significant mitochondrial changes characterized by elevated mitochondrial mass and increased oxygen consumption during activation. These mitochondrial changes were mitigated upon TNF-a blockade. Similar increases in platelet mitochondrial mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF-a 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-a critically regulates megakaryocytes resident in the bone marrow niche and aging-associated platelet hyperreactivity and thrombosis.
AB - 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 a (TNF-a) as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. We further showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF-a 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-a was endogenously increased) and from young mice exposed to exogenous TNF-a exhibited significant mitochondrial changes characterized by elevated mitochondrial mass and increased oxygen consumption during activation. These mitochondrial changes were mitigated upon TNF-a blockade. Similar increases in platelet mitochondrial mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF-a 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-a critically regulates megakaryocytes resident in the bone marrow niche and aging-associated platelet hyperreactivity and thrombosis.
UR - http://www.scopus.com/inward/record.url?scp=85071255350&partnerID=8YFLogxK
U2 - 10.1182/blood.2019000200
DO - 10.1182/blood.2019000200
M3 - Article
C2 - 31311815
AN - SCOPUS:85071255350
VL - 134
SP - 727
EP - 740
JO - Blood
JF - Blood
SN - 0006-4971
IS - 9
ER -