In human macrophages, RvD1 potently blocks production of pro-inflammatory cytokines (e.g., IL-1, IL-8 and CCL2) in a GPR32-dependent Rabbit Polyclonal to ERN2 manner, which could help to prevent further recruitment of inflammatory monocytes142. nutritional and current therapeutic Butylphthalide approaches modulate resolution and propose that harnessing resolution concepts Butylphthalide could potentially lead to the development of new approaches for treating chronic cardiovascular inflammation in a manner that is not host-disruptive. apoptotic cells is required to prevent bystander tissue damage and to set the stage for tissue repair and regeneration, allowing for the return to homeostasis9, 15. Indeed, active clearance of apoptotic cells is a key defining feature of resolution, as failed clearance can lead to cellular necrosis and exacerbated inflammation beyond the initial insult, impeding tissue repair. Macrophages persist in injured tissues longer than short-lived PMN, during which time they are continuously reprogrammed in response to local cues to facilitate tissue repair and orchestrate the delicate balance of Butylphthalide fibrosis16C18. Like innate immune cells, adaptive immune cells also play critical roles in the host response to infection, resolution of inflammation and in tissue repair19, 20. Their accumulation defines the post-resolution phase of the inflammatory response and assures a more rapid response to subsequent exposure to the same antigens19. Interruption of this process at any point (e.g., prolonged leukocyte recruitment and survival, impairments in apoptotic cell removal, alterations in macrophage phenotype switching) could potentially lead to chronic inflammation with resultant tissue damage, excessive fibrosis and loss of function, as is seen in many CVDs like atherosclerosis and HF10, 17, 21C23. Open in a separate window Figure 1 The coordinated temporal events of self-limited acute inflammationThe ideal outcome of an acute inflammatory response is complete resolution. The inflammatory response can be divided into Butylphthalide 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. By its nature, the acute inflammatory response is self-limiting in part because of inherent negative feedback regulation of inflammatory signaling pathways (e.g., transcriptional repressors, endogenous receptor antagonists) when the trigger has been eliminated. However, it has recently become evident that active resolution of inflammation involves the biosynthesis of pro-resolving mediators that, as a genus, are just as diverse as the initiators of inflammation24C33. Thus, critical to determining the fate of an inflammatory response is the balance of pro-inflammatory and pro-resolving mediators that are produced in the exudate in a temporal manner. Traditionally, it has been held that an excess production of pro-inflammatory mediators underlies chronic inflammation34, however, mounting evidence supports the view that disruptions in endogenous pro-resolving circuits may be an equally important mechanism10, 34, 35. These pro-resolving mediators actively terminate the production of pro-inflammatory mediators, but also directly stimulate macrophage phagocytosis of both apoptotic cells and bacteria, promote egress of phagocytes from sites of inflammation, regulate PMN apoptosis, promote chemokine scavenging, and stimulate tissue repair and regeneration9, 36C41. These agonist-based actions distinguish pro-resolving mediators from intrinsic negative feedback pathways and other antagonists that terminate inflammatory signaling pathways. Systems-based approaches have played a crucial role in the identification of the principal mediators of resolution9. As a result, a complex and ever-expanding network of interrelated mediators and the cellular targets and pathways that they engage has been assembled. The discovery of these novel bioactive pro-resolving mediators represents a paradigm shift in our understanding of the dynamic regulation of acute inflammation and has led to a new era of resolution physiology9. Pro-resolving mediators The discovery of bioactive mediators with potent inflammation-resolving actions in experimental models of acute inflammation was a seminal development that provided compelling evidence that resolution is an active process rather than a passive one as traditionally thought. Self-resolving inflammatory exudates were shown to contain structurally unique families of signaling molecules that are temporally produced and when added back in experimental models of acute inflammation, potently.