How inflammation and thrombosis fuel disease and aging: Focus on NETs This R35 0IA application is an extension based on two recently funded NHLBI RO1 grants entitled ?NETS in thrombosis and inflammatory responses? and ?NETs and their modulating enzymes in age-related inflammatory diseases.? For many years, we have conducted a successful research program studying thrombosis and inflammation. Our current emphasis is on newly discovered neutrophil extracellular traps (NETs). Upon neutrophil activation, peptidylarginine deiminase 4 (PAD4) translocates to the nucleus to citrullinate histones. This decondenses chromatin, which is released as NETs. NETs trap microbes but we have shown a dark side of NETs, i.e., they promote thrombosis, inflammation and age-related heart and lung fibrosis. The central hypotheses of our program are: NETs are involved in the formation of a stable organized and vascularized thrombus and breaking up NETs is necessary for thrombolysis. Thrombosis promotes deposition of NETs in the adjacent vessel wall and also in distant organs leading to post-thrombotic syndrome and an increased systemic pro-coagulant and pro-inflammatory state. Aging promotes NET formation and NETs in turn escalate chronic inflammatory and thrombotic diseases. We believe that inhibition of the process of NET formation or destruction of NETs would be beneficial to the host. Finally, we hypothesize that genes regulating NETosis, such as peptidylarginine deiminase 4 (PAD4), impact aging. The work by the ?Wagner Lab? is considered innovative and solid; an objective measure is its high citation. The lab has always been funded by more than one NHLBI grant and for 15 years I was also the PI of a large PPG in Transfusion Biology. However, in the recent difficult funding period too much of my time was spent on securing support for my group. Obtaining prolonged funding would free my time for more mentoring, writing reviews, and collegiate activities. In addition, we now study chronic inflammatory diseases and their impact on aging. These experiments take time and the extended duration of support would assure that we could pursue this exiting research effectively.

Public Health Relevance

We have found that as mice age they activate more and more white blood cells to release from their nuclei highly toxic material, called NETs, which causes both inflammation and thrombosis. Thrombotic events are now the biggest killer in the United States and the prevalence of thrombotic and chronic inflammatory diseases is escalating with the increase in longevity. The goal of this application is to figure out how the release of NETs could be inhibited or NETs destroyed to prevent or better treat thrombosis and also improve the health of our aging population.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Unknown (R35)
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Special Emphasis Panel (ZHL1)
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Kindzelski, Andrei L
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Boston Children's Hospital
United States
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Gavillet, Mathilde; Martinod, Kimberly; Renella, Raffaele et al. (2018) A key role for Rac and Pak signaling in neutrophil extracellular traps (NETs) formation defines a new potential therapeutic target. Am J Hematol 93:269-276
Wong, Siu Ling; Wagner, Denisa D (2018) Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging. FASEB J :fj201800691R
Witsch, Thilo; Martinod, Kimberly; Sorvillo, Nicoletta et al. (2018) Recombinant Human ADAMTS13 Treatment Improves Myocardial Remodeling and Functionality After Pressure Overload Injury in Mice. J Am Heart Assoc 7:
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Krishnamoorthy, Nandini; Douda, David N; Brüggemann, Thayse R et al. (2018) Neutrophil cytoplasts induce TH17 differentiation and skew inflammation toward neutrophilia in severe asthma. Sci Immunol 3:
Mauracher, L-M; Posch, F; Martinod, K et al. (2018) Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients. J Thromb Haemost 16:508-518
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Ponomaryov, Tatyana; Payne, Holly; Fabritz, Larissa et al. (2017) Mast Cells Granular Contents Are Crucial for Deep Vein Thrombosis in Mice. Circ Res 121:941-950
Hayashi, Hideki; Cherpokova, Deya; Martinod, Kimberly et al. (2017) Sirt3 deficiency does not affect venous thrombosis or NETosis despite mild elevation of intracellular ROS in platelets and neutrophils in mice. PLoS One 12:e0188341
Martinod, Kimberly; Witsch, Thilo; Erpenbeck, Luise et al. (2017) Peptidylarginine deiminase 4 promotes age-related organ fibrosis. J Exp Med 214:439-458