Damage-associated molecular patterns (DAMPs) in vascular diseases

Abstract

Research into the role of chronic sterile inflammation (i.e., a prolonged inflammatory state not caused by an infectious agent) in vascular disease progression has continued to grow over the last few decades. DAMPs have a critical role in this research due to their ability to link stress-causing cardiovascular risk factors to inflammatory phenotypes seen in vascular disease. In this mini-review, we will briefly summarize the DAMPs and receptor signaling pathways that have been extensively studied in the context of vascular disease, including TLRs, RAGE, cGAS-STING, and the NLRP3 inflammasome. In particular, we will discuss how these pathways can promote the release of pro-inflammatory cytokines and chemokines as well as vascular remodeling. Next, we will summarize the results of studies that have linked the various pro-inflammatory effects of DAMPs with the phenotypes in the context of vascular diseases, including atherosclerosis, fibrosis, aneurysm, ischemia, and hypertension. Finally, we will discuss some pre-clinical and clinical trials that have targeted DAMPs, their receptors, or the products of their signaling pathways, and discuss the outlook and future directions for the field at large.

Keywords: DAMP; NLRP3; RAGE; TLR; cGAS-STING; vascular disease.

Figure 1

Overview of select DAMP-signaling pathways. Outline of how the TLR, RAGE, NLRP3, and cGAS-STING pathways interact and overlap. See the main text for more detailed description. (Note that while mentioned in the manuscript for completeness, RLR pathways have been omitted from the figure due to limited evidence so far regarding their roles in sterile inflammation in vascular diseases covered in this review).

Figure 2

DAMP effect in atherosclerosis progression. DAMPs have been shown to be released from endothelial cells into the bloodstream due to stresses associated with cardiovascular disease. Once in the bloodstream DAMPs can interact with PRRs and promote plaque progression through (1) causing increased expression of pro-inflammatory cytokines which promotes immune cell recruitment, (2) increasing expression of ICAM-1 and VCAM-1 on endothelial cells which promotes leukocyte adhesion and extravasation, (3) promoting VSMC migration, proliferation, and vascular remodeling phenotypes, and (4) promoting cell death and foam cell conversion of macrophages at the necrotic plaque core.

Figure 3

DAMPs in ischemia/reperfusion diseases. Hypoxia in tissues, caused either by lack of circulation during the transplantation process, or in this case by acute ischemia due to vessel blockage, can cause cellular damage and massive DAMP release. These DAMPs can have local effects of activating PRRs on nearby cells and causing inflammation, immune cell migration, and disruption of endothelial barrier function. Additionally, released DAMPs can flood into the bloodstream upon reperfusion and activate inflammatory responses in distant organs and even systemic inflammatory shock.