Can the TLR-4-Mediated Signaling Pathway Be “A Key Inflammatory Promoter for Sporadic TAA”?

Figure 4

Our model about the pathophysiology of sporadic TAA, the model of the pathway from the double-face. The major risk factors, hypertension, age, and smoking, induce an increased production of reactive oxygen species (ROS) [17–19] and an upregulation of local renin-angiotensin system [16] and the tissue injury, initially involving ECs and subsequently VSMCs. This determines the release of some damage-related products and proteins (i.e., heart shock proteins (HSPs), high-mobility group box-1, low molecular hyaluronic acid, fibronectin fragments, and others), called danger-associated molecular patterns (DAMPs) [20]. DAMPs alert innate/inflammatory immune system interacting with TLR4 mediated signaling pathway, able to recognize both pathogens and endogenous ligands [21, 22]. Originally described as part of the first-line defense against Gram-negative bacteria, the best known member of TLRs, the TLR4, expressed on leukocytes and a large array of tissue and cell types, such as all aortic wall cells (particularly ECs and VSMCs), responds to these signals [23]. As a consequence, TLR4 activates and triggers an inflammatory response [24–28]. In turn, this determines a typical phenotypic switching of EC and VSMC cells due to activation of stress and stretch pathways accompanied by their dysfunction and senescence [27, 28]. In particular, it implies a differential change in their gene expression profile due prevalently of activation of Nuclear Factor-κB (NF-κB) transcription factor and followed by production and release of the so-called arterial-associated senescence secretor phenotype (AASSP) characterized by numerous inflammatory mediators, mitotic and trophic factors, proteoglycans and metalloproteinases (MMP)s, such as MMP-2 and -9, and vasoactive molecules [17, 24–29]. In addition, this also induces the reduction of nitric oxide (NO) [28]. This complex scenario results in modifications of vascular tone and permeability and degradation of components of extracellular matrix (ECM) and elastic fragmentation. VR and MD are, hence, evocated, which can evolve in aneurysm, dissection and rupture of aorta wall [17].