Resolution of Acute Inflammation and the Role of Resolvins in Immunity, Thrombosis, and Vascular Biology

Abstract

Acute inflammation is a host-protective response that is mounted in response to tissue injury and infection. Initiated and perpetuated by exogenous and endogenous mediators, acute inflammation must be resolved for tissue repair to proceed and for homeostasis to be restored. Resolution of inflammation is an actively regulated process governed by an array of mediators as diverse as those that initiate inflammation. Among these, resolvins have emerged as a genus of evolutionarily conserved proresolving mediators that act on specific cellular receptors to regulate leukocyte trafficking and blunt production of inflammatory mediators, while also promoting clearance of dead cells and tissue repair. Given that chronic unresolved inflammation is emerging as a central causative factor in the development of cardiovascular diseases, an understanding of the endogenous processes that govern normal resolution of acute inflammation is critical for determining why sterile maladaptive cardiovascular inflammation perpetuates. Here, we provide an overview of the process of resolution with a focus on the enzymatic biosynthesis and receptor-dependent actions of resolvins and related proresolving mediators in immunity, thrombosis, and vascular biology. We discuss how nutritional and current therapeutic approaches modulate resolution and propose that harnessing resolution concepts could potentially lead to the development of new approaches for treating chronic cardiovascular inflammation in a manner that is not host disruptive.

Keywords: cardiovascular diseases; fatty acids, omega-3; homeostasis; inflammation; lipids.

Figure 1. The coordinated temporal events of self-limited acute inflammation

The ideal outcome of an acute inflammatory response is complete resolution. The inflammatory response can be divided into two general phases: initiation and resolution. Critical to progressing from initiation to resolution is the temporal switch in lipid mediators that are biosynthesized by leukocytes in the tissue; a process known as lipid mediator class switching. The earliest stage of the inflammatory response is marked by tissue edema due to increased blood flow and microvascular permeability and is mediated by the release of pro-inflammatory lipid mediators including the cysteinyl leukotrienes and prostaglandins. Polymorphonuclear neutrophils (PMN) infiltrate in response to lipid mediators including leukotriene B₄ and engulf and degrade pathogens. Subsequently, PMN undergo apoptosis and also switch from releasing pro-inflammatory mediators to pro-resolving mediators (e.g., resolvins) that signal the clearance of apoptotic cells by macrophages in an anti-inflammatory process termed efferocytosis. In addition to promoting efferocytosis, pro-resolving lipid mediators halt further PMN recruitment and stimulate a pro-resolving macrophage phenotype that is important for tissue repair.

Figure 2. Biosynthesis and receptors for resolvins

The family of resolvins is divided primarily into two groups based on the omega-3 polyunsaturated fatty acid (PUFA) from which they are formed. For E-series resolvin biosynthesis, eicosapentaenoic acid (EPA) is utilized as a substrate for acetylated COX-2 or cytochrome P₄₅₀ enzymes, giving rise to a 18-hydroperoxide intermediate that can be converted to either RvE1 or RvE2 by 5-LOX and additional enzymatic transformations, as indicated. Similarly, DHA serves as a substrate for 15-LOX, giving rise to a 17-hydroperoxide intermediate. This intermediate is subsequently converted to RvD1 or RvD2 via 5-LOX, the formation of an epoxide intermediate, and subsequent enzymatic hydrolysis. Monohydroxy fatty acids, 18-HEPE and 17-HDHA, serve as pathway markers for E-series resolvins and D-series resolvins, respectively. Once formed, resolvins elicit their potent biological actions by activating specific G-protein coupled receptors (GPCRs) in a stereoselective manner. RvE1 is an agonist for ERV/ChemR23, while both RvE1 and RvE2 block the actions of pro-inflammatory leukotriene B₄ by binding to its receptor, BLT1. D-series resolvins are agonists for distinct GPCRs, with RvD1 binding to DRV1/GPR32 and ALX/FPR2, and RvD2 binding to GPR18.

Figure 3. Biological actions of resolvins and other SPM related to cardiovascular inflammation

During acute inflammation or infection, SPM are generated during leukocyte:endothelial interactions and directly block PMN chemotaxis. By directly targeting the endothelial cells of the vasculature (e.g., post-capillary venules), SPM also prevent the capture, rolling and adhesion of PMN to the endothelial monolayer and block their extravasation across the endothelium. Additionally, they stimulate production of nitric oxide (NO) and prostacyclin (PGI₂) from endothelial cells. In the tissue, SPM promote the protective actions of leukocytes by enhancing the phagocytosis of bacteria and cellular debris and macrophage efferocytosis of apoptotic PMN. In the context of atherosclerosis, SPM decrease endothelial cell production of leukocyte chemoattractants and adhesion molecules, potentially halting further recruitment of leukocytes to the vessel wall. They also potently prevent platelet aggregation and thrombosis. In the subendothelium, enhanced macrophage efferocytosis and promotion of a resolving macrophage phenotype contributes to a more stable plaque with decreased necrosis. During pathologic inward remodeling (i.e. restenosis), SPM combat neointimal hyperplasia by inhibiting vascular smooth muscle cell (VSMC) proliferation and migration while simultaneously preventing monocyte adhesion and inflammatory signaling.