The Role of Tumor Necrosis Factor Associated Factors (TRAFs) in Vascular Inflammation and Atherosclerosis.

Mark Colin Gissler,Timoteo Marchini,Peter Stachon,Dennis Wolf

doi:10.3389/fcvm.2022.826630

Abstract

TNF receptor associated factors (TRAFs) represent a family of cytoplasmic signaling adaptor proteins that regulate, bundle, and transduce inflammatory signals downstream of TNF- (TNF-Rs), interleukin (IL)-1-, Toll-like- (TLRs), and IL-17 receptors. TRAFs play a pivotal role in regulating cell survival and immune cell function and are fundamental regulators of acute and chronic inflammation. Lately, the inhibition of inflammation by anti-cytokine therapy has emerged as novel treatment strategy in patients with atherosclerosis. Likewise, growing evidence from preclinical experiments proposes TRAFs as potent modulators of inflammation in atherosclerosis and vascular inflammation. Yet, TRAFs show a highly complex interplay between different TRAF-family members with partially opposing and overlapping functions that are determined by the level of cellular expression, concomitant signaling events, and the context of the disease. Therefore, inhibition of specific TRAFs may be beneficial in one condition and harmful in others. Here, we carefully discuss the cellular expression and signaling events of TRAFs and evaluate their role in vascular inflammation and atherosclerosis. We also highlight metabolic effects of TRAFs and discuss the development of TRAF-based therapeutics in the future.

Highlights

TNF receptor associated factors (TRAFs) represent a family of cytoplasmic signaling adaptor proteins that regulate, bundle, and transduce inflammatory signals downstream of TNF- (TNF-Rs), interleukin (IL)-1, Toll-like- (TLRs), and IL-17 receptors
TRAFs are potent regulators of several pro-inflammatory and pro-atherogenic signaling pathways (Figure 4), including these initiated by TNF, IL-1, IL-6, IL-17, and TLRsignaling
Traditional anti-inflammatory therapies aim for the disruption of one inflammatory signaling cascade, either of soluble ligands or receptors by monoclonal antibodies or small molecule inhibitors, which is exemplified by monoclonal antibodies inhibiting IL-1β [11] or IL-6 [12]

Summary

ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE OF ARTERIES

Atherosclerosis is a disease of medium- to large-sized arteries that leads to the build-up of vessel occluding atherosclerotic plaques. TRAFs in Vascular Inflammation evidence of numerous preclinical and clinical studies have stablished that atherosclerosis is a chronic inflammatory and immune-driven disease of the arterial wall [5]. This response involves stromal cells, such as endothelial cells (EC) and smooth muscle cells (SMC), and cells of the innate and adaptive immune system. Preclinical evidence has suggested that TRAFs may represent such inflammatory targets It is well-established that inflammatory signaling cascades are potent modulators of atherosclerosis [19]. It has been proposed that targeting inflammatory signaling cascades downstream of several pro-inflammatory receptors may overcome some of these limitations

TRAFS ARE INTRACELLULAR ADAPTER PROTEINS THAT REGULATE INFLAMMATORY SIGNALING

RANK TACI

TRAFS IN PLATELET FUNCTION AND HOMEOSTASIS

CONCLUSION AND THERAPEUTIC PERSPECTIVE