Therapeutic Potential of Lipoxin A4 in Chronic Inflammation: Focus on Cardiometabolic Disease

Abstract

Several studies have shown that failure to resolve inflammation may contribute to the progression of many chronic inflammatory disorders. It has been suggested targeting the resolution of inflammation might be a novel therapeutic approach for chronic inflammatory diseases, including inflammatory bowel disease, diabetic complications, and cardiometabolic disease. Lipoxins [LXs] are a class of endogenously generated mediators that promote the resolution of inflammation. Biological actions of LXs include inhibition of neutrophil infiltration, promotion of macrophage polarization, increase of macrophage efferocytosis, and restoration of tissue homeostasis. Recently, several studies have demonstrated that LXs and synthetic analogues protect tissues from acute and chronic inflammation. The mechanism includes down-regulation of pro-inflammatory cytokines and chemokines (e.g., interleukin-1β and tumor necrosis factor-α), inhibition of the activation of the master pro-inflammatory pathway (e.g., nuclear factor κ-light-chain-enhancer of activated B cells pathway) and increased release of the pro-resolving cytokines (e.g., interleukin-10). Three generations of LXs analogues are well described in the literature, and more recently a fourth generation has been generated that appears to show enhanced potency. In this review, we will briefly discuss the potential therapeutic opportunity provided by lipoxin A₄ as a novel approach to treat chronic inflammatory disorders, focusing on cardiometabolic disease and the current drug development in this area.

Figure 1

An overview of immune cell infiltration and pro-inflammatory/pro-resolving mediator release in the setting of inflammation. The initiation phase of inflammation is characterized by the release of pro-inflammatory mediators and the accumulation of neutrophils. During the resolution phase, anti-inflammatory and pro-resolving mediators (e.g., LXs, Rvs, MaRs, and protectins) are released. Pro-resolving mediators limit neutrophil infiltration and promote M1-like to M2-like macrophage phenotype switching. The M2-like macrophages exert an anti-inflammatory effect through macrophage efferocytosis and the release of anti-inflammatory cytokines such as TGF-β₁ and IL-10. IL = interleukin; TNF-α = tumor necrosis factor-α; LTs = leukotrienes; GM-CSF = granulocyte-macrophage colony-stimulating factor; VCAM = vascular cell adhesion molecule; ICAM = intercellular adhesion molecule; Tx = thromboxane; PGs = prostaglandins; LXs = lipoxins; Rvs = resolvins; MaRs = maresins; TGF-β = transforming growth factor-β; VEGF = vascular endothelial growth factor; PAF = platelet-activating factor; PGE₂ = prostaglandin E₂. The figure was adapted from ref (3), copyright 2011, American Chemical Society. This schema was created using images provided by Inkscape and Servier Medical Art by Servier (https://smart.servier.com/image-set-download/), licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licences/by/3.0/).

Figure 2

Biosynthesis of lipoxins. Three major pathways involved in the synthesis of LXs involving LOX, including 5-LOX, 15-LOX, and 12-LOX. They all contribute to the synthesis of LXs from arachidonic acid. AA = arachidonic acid; LOX = lipoxygenase; 15-HPETE = 15-hydroxy-peroxyeicosatetraenoic acid; COX-2 = cyclooxygenase-2; LTA₄ = leukotriene A₄. This schema was created using images provided by Inkscape.

Figure 3

Function and distribution of FPRs in different cell types. FPR1 and ALX/FPR2 are widely distributed on the membrane of monocytes, eosinophils, neutrophils, and epithelial cells. Pathogen-associated molecular patterns (PAMPs), DAMPS, or pro-resolving mediators can activate FPRs. The common function of FPRs is regulating the resolution of inflammation. Image adapted from refs ( and 89). Copyright 2015, 2018, Elsevier. This schema was created using images provided by Inkscape.

Figure 4

The bioactions of LXA₄ in a self-limiting inflammatory process. Dashed red lines indicate inhibition of LXA₄, and green solid lines indicate the pro-resolving functions of LXA₄. Data adapted from refs (, , and 45). The schema was created using images provided by Inkscape and Servier Medical Art by Servier (https://smart.servier.com/image-set-download/), licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licences/by/3.0/).