Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases

Abstract

Inflammation is associated with the development of diseases characterized by altered nutrient metabolism. Although an acute inflammatory response is host-protective and normally self-limited, chronic low-grade inflammation associated with metabolic diseases is sustained and detrimental. The resolution of inflammation involves the termination of neutrophil recruitment, counterregulation of proinflammatory mediators, stimulation of macrophage-mediated clearance, and tissue remodeling. Specialized proresolving lipid mediators (SPMs)-resolvins, protectins, and maresins-are novel autacoids that resolve inflammation, protect organs, and stimulate tissue regeneration. Here, we review evidence that the failure of resolution programs contributes to metabolic diseases and that SPMs may play pivotal roles in their resolution.

Figure 1. Specialized pro-resolving lipid mediator biosynthesis during resolution of inflammation

(A) Complete resolution is the ideal outcome of inflammation, although if not properly regulated can lead to chronic inflammation, fibrosis and loss of function. Inflammation and its resolution involves a temporal series of leukocyte trafficking events coupled with lipid mediator class switching, in which pro-inflammatory lipid mediators signal the generation of pro-resolving lipid mediators. (B) Depiction of classic and novel lipid mediator families generated from essential omega-6 (n-6) and omega-3 (n-3) fatty acids, arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). (C) Abbreviated biosynthetic pathways and structures of resolvins, protectins and maresins generated enzymatically from DHA. Their complete stereochemical structures are established; see text for details. LOX-lipoxygenase, RvD1-resolvin D1, PD1-protectin D1, MaR1-maresin 1.

Figure 2. Pro-resolving receptors and biological actions of SPM

E-series resolvins (RvE1 and RvE2) are agonists for ChemR23/ERV and antagonists for the leukotriene B₄ receptor, BLT-1. Lipoxin A₄ (LXA₄) and D-series resolvins, RvD1, RvD3 and RvD5 (RvD1 structure shown) are agonists for GPR32/DRV1 and ALX/FPR2. Acting via these specific receptors, SPM elicit their biological actions on leukocytes, which include the attenuation of polymorphonuclear neutrophil (PMN) trafficking, activation and inflammatory gene transcription, as well as the stimulation of macrophage phagocytosis of both apoptotic cells and bacteria.

Figure 3. Altered resolution of inflammation in diabetic wounds

(A) Cellular events during a normal acute inflammatory response, depicting the rapid macrophage-dependent clearance of apoptotic neutrophils (PMN). Established resolution indices are shown, with ψ_max representing maximum PMN infiltration, T_max representing the time point at which PMN reach their maximum levels, T₅₀ representing the time point at which PMN decline to half of their maximum value and R_i representing the resolution interval, the period of time during which PMN decrease to half of their maximum value; see text for details. (B) Altered resolution of acute inflammation in the context of obesity and diabetes in which PMN apoptosis is delayed and macrophage efferocytosis is defective. (C) Depiction of defects in the wound-healing program in diabetes, including persistent leukocyte and apoptotic cell accumulation and defective wound closure. (D) Enhancement of wound healing in diabetes by SPM by promoting macrophage-mediated apoptotic cell clearance and re-epithelialization.

Figure 4. Biosynthesis and biological role of SPM in adipose tissue

In the adipose tissue, the major long chain polyunsaturated fatty acids, arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid, and, are endogenously converted into potent anti-inflammatory and pro-resolving SPM lipoxin A₄, resolvin E1, protectin D1 and resolvin D1. In inflamed adipose tissue, these mediators evoke cell-specific regulatory actions on adipokine expression and/or secretion by adipocytes and macrophages. Resolvin D1 also promotes macrophage polarization toward the anti-inflammatory M2 phenotype. A section of adipose tissue immunostained with an F4/80 antibody, depicting a remarkable infiltration of macrophages forming “crown-like” structures within surrounding adipocytes, is shown in the upper right corner. COX-2: cyclooxygenase-2; Cyt P450: cytochrome P450; LOX: lipoxygenase; IL: interleukin; TNFα: tumor necrosis factor α; MCP-1: monocyte chemoattractant protein-1.