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

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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.

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Most cited references 47

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Functionally Distinct Subsets of Lineage-Biased Multipotent Progenitors Control Blood Production in Normal and Regenerative Conditions.

Eric Pietras, Damien Reynaud, Yoon-A Kang … (2015)

Despite great advances in understanding the mechanisms underlying blood production, lineage specification at the level of multipotent progenitors (MPPs) remains poorly understood. Here, we show that MPP2 and MPP3 are distinct myeloid-biased MPP subsets that work together with lymphoid-primed MPP4 cells to control blood production. We find that all MPPs are produced in parallel by hematopoietic stem cells (HSCs), but with different kinetics and at variable levels depending on hematopoietic demands. We also show that the normally rare myeloid-biased MPPs are transiently overproduced by HSCs in regenerating conditions, hence supporting myeloid amplification to rebuild the hematopoietic system. This shift is accompanied by a reduction in self-renewal activity in regenerating HSCs and reprogramming of MPP4 fate toward the myeloid lineage. Our results support a dynamic model of blood development in which HSCs convey lineage specification through independent production of distinct lineage-biased MPP subsets that, in turn, support lineage expansion and differentiation.

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Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation.

Luc Boudreau, Anne-Claire Duchez, Nathalie Cloutier … (2014)

Mitochondrial DNA (mtDNA) is a highly potent inflammatory trigger and is reportedly found outside the cells in blood in various pathologies. Platelets are abundant in blood where they promote hemostasis. Although lacking a nucleus, platelets contain functional mitochondria. On activation, platelets produce extracellular vesicles known as microparticles. We hypothesized that activated platelets could also release their mitochondria. We show that activated platelets release respiratory-competent mitochondria, both within membrane-encapsulated microparticles and as free organelles. Extracellular mitochondria are found in platelet concentrates used for transfusion and are present at higher levels in those that induced acute reactions (febrile nonhemolytic reactions, skin manifestations, and cardiovascular events) in transfused patients. We establish that the mitochondrion is an endogenous substrate of secreted phospholipase A2 IIA (sPLA2-IIA), a phospholipase otherwise specific for bacteria, likely reflecting the ancestral proteobacteria origin of mitochondria. The hydrolysis of the mitochondrial membrane by sPLA2-IIA yields inflammatory mediators (ie, lysophospholipids, fatty acids, and mtDNA) that promote leukocyte activation. Two-photon microscopy in live transfused animals revealed that extracellular mitochondria interact with neutrophils in vivo, triggering neutrophil adhesion to the endothelial wall. Our findings identify extracellular mitochondria, produced by platelets, at the midpoint of a potent mechanism leading to inflammatory responses. © 2014 by The American Society of Hematology.

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Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment

Larisa V Kovtonyuk, Kristin Fritsch, Xiaomin Feng … (2016)

All hematopoietic and immune cells are continuously generated by hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) through highly organized process of stepwise lineage commitment. In the steady state, HSCs are mostly quiescent, while HPCs are actively proliferating and contributing to daily hematopoiesis. In response to hematopoietic challenges, e.g., life-threatening blood loss, infection, and inflammation, HSCs can be activated to proliferate and engage in blood formation. The HSC activation induced by hematopoietic demand is mediated by direct or indirect sensing mechanisms involving pattern recognition receptors or cytokine/chemokine receptors. In contrast to the hematopoietic challenges with obvious clinical symptoms, how the aging process, which involves low-grade chronic inflammation, impacts hematopoiesis remains undefined. Herein, we summarize recent findings pertaining to functional alternations of hematopoiesis, HSCs, and the bone marrow (BM) microenvironment during the processes of aging and inflammation and highlight some common cellular and molecular changes during the processes that influence hematopoiesis and its cells of origin, HSCs and HPCs, as well as the BM microenvironment. We also discuss how age-dependent alterations of the immune system lead to subclinical inflammatory states and how inflammatory signaling might be involved in hematopoietic aging. Our aim is to present evidence supporting the concept of “Inflamm-Aging,” or inflammation-associated aging of hematopoiesis.

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Author and article information

Journal

Title: Blood

Publisher: American Society of Hematology

ISSN (Print): 0006-4971

ISSN (Electronic): 1528-0020

Publication date Created: August 29 2019

Publication date (Print): August 29 2019

Volume: 134

Issue: 9

Pages: 727-740

Affiliations

[1 ]Center for Cancer and Blood Disorders, Department of Pediatrics and

[2 ]Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO;

[3 ]Irish Center for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland;

[4 ]Department of Mechanical Engineering, Colorado State University, Fort Collins, CO;

[5 ]Cardiovascular Pulmonary Research Laboratory, Department of Pediatrics and

[6 ]Cardiovascular Pulmonary Research Laboratory, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO;

[7 ]Molecular Medicine Program and

[8 ]Department of Internal Medicine, University of Utah, Salt Lake City, UT;

[9 ]Department of Biochemistry and Molecular Genetics and

[10 ]Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO;

[11 ]Department of Internal Medicine, University of Washington, Seattle, WA;

[12 ]Division of Geriatrics, University of Utah, Salt Lake City, UT;

[13 ]Geriatric Research, Education, and Clinical Center, George E. Wahlen Department of Veterans Affairs Medical Center (VAMC), Salt Lake City, UT;

[14 ]División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, México;

[15 ]Department of Pathology and Laboratory Medicine, Children’s Hospital Colorado, Aurora, CO; and

[16 ]Department of Pathology, University of Utah, Salt Lake City, UT

Article

DOI: 10.1182/blood.2019000200

PMC ID: 6716075

PubMed ID: 31311815

SO-VID: cc3c25f1-352d-4684-8d50-5770976ef390

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

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Aging Pathobiology and Therapeutics

Most cited references 47

Functionally Distinct Subsets of Lineage-Biased Multipotent Progenitors Control Blood Production in Normal and Regenerative Conditions.

Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation.

Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment

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Cited by 96

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