The role of tumor necrosis associated factor (TRAF)-1 in cardio-metabolic disease

Abstract: Cardiovascular disease (CVD), such as atherosclerosis, myocardial infarction (MI) and stroke, represents the most common cause of death globally and is driven by a cluster of risk factors – obesity, hypertension, hyperlipidemia, and insulin resistance – that is referred to as the Metabolic Syndrome (MS). Chronic, low-grade inflammation fuels not only atherosclerosis, but also critically contributes to adipose tissue dysfunction in MS. Inflammatory pathways also determine acute complications of atherosclerosis, such as arterial thrombosis causing MI and stroke. Despite their potent role in mediating CVD, common underlying pathways that simultaneously drive the development of risk factors, atherosclerosis, and its complications have only been poorly defined. Here, hypothesized that TRAF-1, a signal adapter that bundles pro-inflammatory signaling from TNFRs-, IL1R-, and TLRs in an inhibitory fashion is such a modulator. By employing three different, but complementary approaches I found that:
(1) TRAF-1 is a potent modulator of adipose tissue remodeling. A genetic deficiency of TRAF-1 improved facets of the MS in mice, such as obesity, insulin resistance, and dyslipidemia. Mechanistically, I identified increased lipolysis in adipocytes and enhanced energy expenditure by an adrenergic, UCP-1-dependent mechanism. Surprisingly, TRAF-1-/- mice exhibited a hyper-inflammatory phenotype in adipose tissue, confirming TRAF-1’s function as inhibitory signaling molecule in inflammation. These results further nourish the notion that inflammatory cell infiltration does not ultimately cause dysmetabolism under every circumstances.
(2) TRAF-1 was previously reported to attenuate inflammation in atherosclerosis by inhibiting leukocyte recruitment. In contrast to these findings, I observed that – in the absence of atherosclerosis – TRAF-1-/- promoted leukocyte recruitment by a direct up-regulation of adhesion molecules on myeloid cells, but also by augmenting the pool of circulating monocytes. These effects were caused by an inhibition of TRAF-1- regulated apoptosis and an activation of proliferation of hematopoeitic stem cells and monocyte progenitors in the bone marrow. Under steady-state conditions, however, TRAF-1-/- was a negative regulator of proliferation and leukocyte mobilization from the bone marrow, proposing a dual role of TRAF-1 in health and disease.
(3) TRAF-1 is constitutively expressed by platelets and human coronary thrombi and contributes to haemostatic and thrombotic pathways in mice. After stimulation with platelet agonists, TRAF-1-/- platelets were less responsive and caused a delayed formation of arterial thrombi in vivo. In addition, bleeding time in TRAF-1-/- mice was prolonged, an effect independent on TRAF-1 expression in platelets, but dependent on expression in non-hematopoeitic cells.
Taken together, I show that TRAF-1 is a potent modulator of inflammatory signaling in cardiovascular pathologies, contributing to leukocyte recruitment, inflammatory hematopoiesis, adipose tissue inflammation, and thrombosis. My results, however, indicate that the function of TRAF-1 is cell- and tissue-specific with a proposed inhibitory function in inflammatory signaling in macrophages and endothelial cells, but an activating effect on inflammatory and metabolic pathways in platelets and adipocytes, respectively. These findings not only identify TRAF1- signaling as potent mediator of anti- and pro-inflammatory pathways in these conditions, but also help to understand the partially opposing role of inflammation in cardiovascular risk factor development, pathologies, and complications. Finally, my results call for the development of cell-type, and disease-specific treatment strategies that can selectively modulate TRAF-1 functioning in cardiovascular disease

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Universität Freiburg, Dissertation, 2017

Klassifikation und Themen

• Schlagwort: Tumor-Nekrose-Faktor ; Kardiovaskuläre Krankheit

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2017
• Urheber: Anto Michel, Nathaly
• Beteiligte Personen und Organisationen: Zirlik, Andreas ; Grosschedl, Rudolf ; Albert-Ludwigs-Universität Freiburg. Fakultät für Biologie

Weitere Informationen

• DOI: 10.6094/UNIFR/12908
• URN: urn:nbn:de:bsz:25-freidok-129084
• Rechteinformation: Kein Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 14.08.2025, 10:44 MESZ