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Inflammaging and platelet hyperreactivity: A new therapeutic target?

2020; Elsevier BV; Volume: 18; Issue: 1 Linguagem: Inglês

10.1111/jth.14670

1538-7933

Joshua Price, Janet M. Lord, Paul Harrison,

Inflammasome and immune disorders

Inflammaging is defined as a chronic low‐grade and systemic inflammation that accelerates the process of biological aging and is associated with many age‐related diseases including cardiovascular disease (CVD), rheumatoid arthritis (RA), myeloproliferative disease, inflammatory bowel disease, Alzheimer's disease, and frailty.1.Franceschi C. Garagnani P. Parini P. Giuliani S.A. Inflammaging: a new immune–metabolic viewpoint for age‐related diseases.Nat Rev Endocrinol. 2018; 14: 576-590Crossref PubMed Scopus (1010) Google Scholar There are many contributors to this inflammatory status including adiposity, senescent cells, and aged monocytes, which secrete a low level of pro‐inflammatory cytokines in the absence of antigenic challenge.2.Pinti M. Appay V. Campisi J. et al.Aging of the immune system: focus on inflammation and vaccination.Eur J Immunol. 2016; 46: 2286-2301Crossref PubMed Scopus (237) Google Scholar Senescent cells are metabolically active, non‐proliferative, but highly pro‐inflammatory cells that accumulate in tissue and organs throughout the body in association with age‐related decline in the innate immune system's clearance capability (eg, natural killer cells).3.Prata L. Ovsyannikova I.G. Tchkonia T. Kirkland J.L. Senescent cell clearance by the immune system: Emerging therapeutic opportunities.Semin Immunol. 2019; : 101275Google Scholar Aging is of course strongly associated with increased risk of CVD, the leading cause of worldwide mortality.4.Roth G.A. Johnson C. Abajobir A. et al.Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015.J Am Coll Cardiol. 2017; 70: 1-25Crossref PubMed Scopus (2078) Google Scholar Platelets play a vital role in normal hemostasis and are key players in the pathogenesis of atherothrombosis. These abundant anuclear cells not only directly mediate thrombosis but are now recognized as true inflammatory cells that can both propagate inflammatory responses and directly respond to inflammation.5.Morrell C.N. Aggrey A.A. Chapman L.M. Modjeski K.L. Emerging roles for platelets as immune and inflammatory cells.Blood. 2014; 123: 2759-2767Crossref PubMed Scopus (458) Google Scholar Antiplatelet drugs are therefore important for the prevention of thrombotic events in high‐risk patients with established CVD. Intrinsic platelet reactivity varies between individuals and increases with age.6.Alfredsson J. Swahn E. Gustafsson K.M. et al.Individual long‐term variation of platelet reactivity in patients with dual antiplatelet therapy after myocardial infarction.Platelets. 2019; 30: 572-578Crossref Scopus (4) Google Scholar, 7.Troussard X. Vol S. Cornet E. et al.Full blood count normal reference values for adults in France.J Clin Pathol. 2014; 67: 341-344Crossref Scopus (44) Google Scholar In older individuals, platelet hyperreactivity therefore occurs more commonly and is associated with chronic age‐related CVD, comorbidities, and mortality. Furthermore, underlying platelet reactivity can significantly affect responsiveness to antiplatelet drugs used to prevent thrombosis.8.Kumar A. Kao J. Platelet resistance to antiplatelet drugs.Recent Pat Cardiovasc Drug Discov. 2009; 4: 98-108Crossref Scopus (10) Google Scholar, 9.Jagroop I.A. Matsagas M.I. Geroulakos G. Mikhailidis D.P. The effect of clopidogrel, aspirin and both antiplatelet drugs on platelet function in patients with peripheral arterial disease.Platelets. 2004; 15: 117-125Crossref PubMed Scopus (70) Google Scholar, 10.Yee D.L. Sun C.W. Bergeron A.L. Dong J.F. Bray P.F. Aggregometry detects platelet hyperreactivity in healthy individuals.Blood. 2005; 106: 2723-2729Crossref PubMed Scopus (174) Google Scholar Although the mechanisms that govern platelet reactivity in age are multifactorial (eg, genetics, poor glucose control, dyslipidemia, and oxidative stress), the precise pathways linking inflammaging to platelet function are not yet fully defined. Despite this, inflammatory cytokines such as TNF‐α, IL‐1β, IL‐8, and IL‐6 are elevated with age and associated with a suite of inflammatory conditions and CVD. Inflammatory mediators can also modify platelet function. For example, IL‐6 has been implicated in altering the megakaryocytic/platelet axis, potentially leading to polyploidization and consequent thrombopoiesis with a shift toward a more prothrombotic phenotype and a higher mean platelet volume (MPV).11.Burstein S.A. Peng J. Friese P. et al.Cytokine‐induced alteration of platelet and hemostatic function.Stem Cells. 1996; 14: 154-162Crossref PubMed Scopus (64) Google Scholar Furthermore, platelets express GP130, which can bind to complexes of IL‐6 and soluble IL‐6 receptor α (sIL‐6Rα) to further prime platelets via transcellular signalling and further increase their reactivity during inflammation.12.Houck K.L. Yuan H. Tian Y. et al.Physical proximity and functional cooperation of glycoprotein 130 and glycoprotein VI in platelet membrane lipid rafts.J Thromb Haemost. 2019; 17: 1500-1510Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar The incidence of CVD as a comorbidity in age‐related diseases is also high suggesting a common pathophysiology mediated by inflammatory cytokines. Acquired platelet hyperreactivity is thus an important modifiable phenotype that forms an attractive therapeutic target for an aging population at risk of chronic diseases mediated by inflammaging. A recent paper by Davizon‐Castillo et al13.Davizon‐Castillo P. McMahon B. Aguila S. et al.TNF‐α–driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging.Blood. 2019; 134: 727-740Crossref PubMed Scopus (124) Google Scholar in Blood now further establishes how platelet hyperreactivity is driven by chronic inflammation. An excellent commentary on this article by Podrez14.Podrez E. Platelet hyperreactivity: a new twist in old mice.Blood. 2019; 134: 723-724Crossref Scopus (3) Google Scholar was also in the same issue. This research builds upon a series of studies from some of the authors studying altered platelet function in aging. The authors now demonstrate that the pro‐inflammatory cytokine TNF‐α drives metabolic reprogramming of megakaryocytes (MK), platelet mitochondrial dysfunction, and platelet hyperreactivity as part of normal aging in humans and mice. Furthermore, exogenous administration of TNF‐α to young mice also recapitulated the aging platelet phenotype. Older mice had increased plasma levels of TNF‐α and increased platelet counts but with no change in leukocyte count, in agreement with previous studies.15.Culmer D. Diaz J. Hawley A. et al.Circulating and vein wall P‐selectin promote venous thrombogenesis during aging in a rodent model.Thromb Res. 2013; 131: 42-48Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 16.Dayal S. Wilson K. Motto Jr, D. Miller F. Chauhan A. Lentz S. Hydrogen peroxide promotes aging‐related platelet hyperactivation and thrombosis.Circulation. 2013; 127: 1308-1316Crossref PubMed Scopus (130) Google Scholar Upon stimulation, washed murine platelets from older mice exhibited heightened ⍺IIbβ3 integrin expression, increased phosphatidylserine exposure, and formed larger thrombi more rapidly on collagen‐coated slides. Interestingly it has been shown previously that TNF‐α levels are much higher in the bone marrow compartment when compared to plasma in aged mice suggesting that local bone marrow MKs will be more susceptible to inflammaging.17.Puchta A. Naidoo A. Verschoor C.P. et al.TNF drives monocyte dysfunction with age and results in impaired anti‐pneumococcal immunity.PLoS Pathog. 2016; 12Crossref Scopus (88) Google Scholar There is good evidence implicating monocytes as a source of both bone marrow and systemic increases in pro‐inflammatory cytokine levels, including TNF‐α.18.Parameswaran N. Patial S. Tumor necrosis factor‐alpha signaling in macrophages.Crit Rev Eukaryot Gene Expr. 2010; 20: 87-103Crossref PubMed Scopus (892) Google Scholar Furthermore, both this paper and other studies have shown that monocyte derived TNF‐α is implicated in the increased platelet count, reactivity, and mitochondrial mass in patients with myeloproliferative disease.19.Taylor D.D. Senhauser D.A. Cavazos F. Thrombocytopathy associated with nonleukemic megakaryocytic myelosis. Functional and fine structure observations of the abnormal platelets.Am J Clin Pathol. 1968; 49: 662-670Crossref Scopus (3) Google Scholar, 20.Hattori A. Koike K. Ito S. Matsuoka M. Static and functional morphology of the pathological platelets in primary myelofibrosis and myeloproliferative syndrome.Ser Haematol. 1975; 8: 126-150Google Scholar It is intriguing that activated platelets also avidly interact with and bind to monocytes, further resulting in significant upregulation of the production of inflammatory cytokines.21.Stephen J. Emerson B. Fox K.A. Dransfield I. The uncoupling of monocyte‐platelet interactions from the induction of proinflammatory signaling in monocytes.J Immunol. 2013; 191: 5677-5683Crossref PubMed Scopus (45) Google Scholar In a related study by some of the same authors, aging platelets have been shown to not only exhibit altered transcriptomes but to contain a 9‐fold increase (compared to younger adults) in levels of granzyme A, a serine protease not previously identified in human platelets.22.Campbell R.A. Franks Z. Bhatnagar A. et al.Granzyme A in human platelets regulates the synthesis of proinflammatory cytokines by monocytes in aging.J Immunol. 2018; 200: 295-304Crossref PubMed Scopus (49) Google Scholar This was also shown to upregulate inflammatory cytokine synthesis (eg, IL‐8 and MCP‐1) in monocytes via TLR‐4 and caspase 1. Although TNF‐α levels were not reported in that study, it is possible that there could be significant amplification of cytokine production and platelet reactivity through this pathway in aging.23.Montenont E. Rondina M.T. Campbell R.A. Altered functions of platelets during aging.Curr Opin Hematol. 2019; 26: 336-342Crossref Scopus (19) Google Scholar Changes in platelet reactivity are further supported by the increase in platelet‐derived products measured in plasma in healthy older participants, and further increases in the context of arterial disease including alpha granule contents and platelet‐derived microparticles.24.Lebas H. Yahiaoui K. Martos R. Boulaftali Y. Platelets Are at the Nexus of Vascular Diseases.Front Cardiovasc Med. 2019; 6: 132Crossref Scopus (35) Google Scholar The increase in platelet‐derived microparticles may in turn accentuate the monocyte pro‐inflammatory phenotype and encourage a thrombo‐inflammatory cascade effect.25.Chimen M. Evryviadou A. Box C. et al.Appropriation of GPIbα from platelet‐derived extracellular vesicles supports monocyte recruitment in systemic inflammation.Haematologica. 2019; Google Scholar Aging‐associated transcriptional changes in MKs were measured at the single cell level. In addition to identifying temporal clusters of MKs that represent maturation status, the authors identified key pathways that were differentially regulated with age. Metabolic pathways and mitochondrial dysfunction were implicated as key age‐associated changes. This may align with the observed increase of mitochondrial mass in patients with myeloproliferative disease, which is associated with chronic inflammation, with TNF‐α strongly implicated. The single most highly upregulated transcript in older mouse MKs was class 1A aldehyde dehydrogenase (ALDH1A), which was also shown to be highly expressed in platelets. Metabolomic analysis also highlighted elevated pentose phosphate pathway intermediates. Increased ALDH1A and elevated pentose phosphate pathway activity is indicative of increased oxidative stress and is probably an attempted compensatory response to mitigate increased oxidative stress due to damage from free radicals and inflammation‐associated damage. The increased reactivity of aged platelets may be due to the increased metabolic activity in resting aged platelets. Increased mitochondrial mass may also result in increased release of microparticle associated and free mitochondria upon platelet activation further exacerbating systemic inflammation.26 Chronic exposure to TNF‐α in young mice over the course of 20 days also promoted a transition to the older MK transcriptome and recapitulated platelet hyperreactivity and the increased platelet mass observed in older mice. Strikingly the authors show that TNF‐α‐ blockade in older mice over the course of 10 days could resolve platelet hyperreactivity and restored normal αIIbβ3 expression in response to thrombin. TNF‐α blockade reduced mitochondria mass but did not reduce platelet count. The TNF‐α pathway was essential for the development of platelet hyperreactivity and increased mitochondrial mass as illustrated by the lack of effect of exogenous administration of TNF‐α to TNF receptor deficient (p55/p75 KO) mice. Indeed bulk RNA‐seq analysis confirmed that the MKs from old mice were transcriptionally homogeneous and to MKs from young mice exposed to TNF‐α. For the first time a well‐established causative link between inflammaging and platelet associated hyperreactivity has been demonstrated. This opens the door to further probing TNF‐α inhibition as a possible adjunct to existing preventative measures (eg, antiplatelet drugs) to further reduce thrombotic risk and CVD. Proof of concept has been shown in RA patients receiving anti‐TNF‐α therapy resulting in a reduction in inflammation and platelet reactivity.26.Boudreau L.H. Duchez A.C. Cloutier N. et al.Platelets release mitochondria serving as substrate for bactericidal group IIA‐secreted phospholipase A2 to promote inflammation.Blood. 2014; 124: 2173-2183Crossref PubMed Scopus (379) Google Scholar, 27.Gasparyan A.Y. Kitas G.D. Platelets in rheumatoid arthritis: exploring the anti‐inflammatory and antithrombotic potential of TNF inhibitors.Ann Rheum Dis. 2016; 75: 1426-1427Crossref Scopus (7) Google Scholar The increased incidence of CVD associated with RA also supports the importance of the thrombo‐inflammatory pathways outlined by Davizon‐Castillo et al. However, long‐term use of TNF‐α inhibitors has been associated with an adverse safety profile in RA trials.28.Mac Mullan P.A. Peace A.J. Madigan A.M. Tedesco A.F. Kenny D. McCarthy G.M. Platelet hyper‐reactivity in active inflammatory arthritis is unique to the adenosine diphosphate pathway: a novel finding and potential therapeutic target.Rheumatology. 2010; 49: 240-245Crossref PubMed Scopus (33) Google Scholar Interestingly, the safety profile of TNF‐α inhibitors increases for ankylosing spondylitis; these patients are typically younger and receive monotherapy so may be a better cohort to establish a true safety profile.28.Mac Mullan P.A. Peace A.J. Madigan A.M. Tedesco A.F. Kenny D. McCarthy G.M. Platelet hyper‐reactivity in active inflammatory arthritis is unique to the adenosine diphosphate pathway: a novel finding and potential therapeutic target.Rheumatology. 2010; 49: 240-245Crossref PubMed Scopus (33) Google Scholar Nevertheless, identification of this inflammatory pathway is an exciting advance and may lead to new therapeutics. This research further emphasizes the interplay among aging, platelets, and monocytes that results in inflammaging, platelet hyperreactivity, and immunothrombosis. None of the authors has any conflict of interest. Joshua Price, Janet Lord, and Paul Harrison prepared the manuscript.