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

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.

Curcumenol Mitigates the Inflammation and Ameliorates the Catabolism Status of the Intervertebral Discs In Vivo and In Vitro via Inhibiting the TNFα/NFκB Pathway

“…Through RNA-seq, we found the expression of several genes involved in inflammatory pathways, especially the TNF signaling pathway and Toll-like receptor signaling pathway manifested distinct changes, among which the TNF receptor associated factors (TRAFs) family, the chemokine CXC motif ligands (CXCLs) family, and IL1 receptor-like 1 (IL1RL1) draws our great attention. TRAF3 is a kind of cytoplasmic signaling adaptor protein that participates in the signal transduction of several important inflammatory pathways, such as NF-κB pathways, TNF signaling pathway, and Toll-like receptor signaling pathway, thus playing a pivotal role in regulating cell proliferation, apoptosis, and inflammatory response ( Häcker et al, 2011 ; Zhou et al, 2021 ; Gissler et al, 2022 ; Wu et al, 2022 ). It was reported that the expression of CXCL10 manifested a positive correlation with the severity of IVDD due to its chemotactic function of recruiting immune cells ( Jacobsen et al, 2020 ).…”

Role of CD40(L)-TRAF signaling in inflammation and resolution—a double-edged sword

“…Overexpression of TRAF3 prevents CD40-induced endothelial cell activation and inhibits the expression of pro-inflammatory cytokines ( Urbich et al, 2001 ). It seems that TRAF4 does not affect the immune cell development and is not involved in vascular inflammation and/or atherosclerosis ( Gissler et al, 2022 ). TRAF4 is involved in more developmental processes like the formation of the respiratory upper tract ( Shiels et al, 2000 ).…”

“…TRAF6 also promotes JNK and p38 MAPK signaling cascades through binding to TRAF2 ( Baud et al, 1999 ). The deficiency of TRAF6 in mice has a serve impact of the immune system: mice lacking TRAF6 show inflammatory cell accumulation in organs, thymic atrophy as well as lack of secondary lymphatic organs ( Akiyama et al, 2005 ; Gissler et al, 2022 ). The lack of CD40-TRAF6 binding leads to reduced inflammatory cytokine production resulting in the ameliorated progression of atherosclerosis compared to CD40-TRAF2/3/5 deficient mice.…”

“…In contrast, CD40L-CD40-TRAF2/3/5 signaling seems to have a more regulatory function in the immune system and may contribute to resolution. Regarding TRAF7 (74 kDa) and its role in inflammation or vascular disease nothing has been published so far ( Gissler et al, 2022 ). A more detailed overview concerning the role of all TRAF proteins and their role in vascular inflammation and atherosclerosis has been published ( Gissler et al, 2022 ).…”

Role of tumor necrosis factor receptor-associated factor 5 in B- and T-lymphocytes

“…To date, seven members numbered sequentially TRAF1 through TRAF7, have been identified in the TRAF family. TRAF molecules are a family of signaling adapters that play vital roles in regulating cellular signaling not only by members of the TNFRSF and the Toll-like receptor (TLR)/interleukin-1 (IL-1) receptor superfamily but also by unconventional receptors for cytokines including IL-6 [2][3][4][5][6][7][8]. Unlike the non-conventional TRAF7, TRAF1 to TRAF6 share the conserved C-terminal TRAF domain, which binds to the cytoplasmic domains of a range of cell surface receptors (Figure 1).…”