Lipoxins: resolutionary road

Abstract

The resolution of inflammation is an active process controlled by endogenous mediators with selective actions on neutrophils and monocytes. The initial phase of the acute inflammatory response is characterized by the production of pro-inflammatory mediators followed by a second phase in which lipid mediators with pro-resolution activities may be generated. The identification of these mediators has provided evidence for the dynamic regulation of the resolution of inflammation. Among these endogenous local mediators of resolution, lipoxins (LXs), lipid mediators typically formed during cell-cell interaction, were the first to be recognized. More recently, families of endogenous chemical mediators, termed resolvins and protectins, were discovered. LXs and aspirin-triggered LXs are considered to act as 'braking signals' in inflammation, limiting the trafficking of leukocytes to the inflammatory site. LXs are actively involved in the resolution of inflammation stimulating non-phlogistic phagocytosis of apoptotic cells by macrophages. Furthermore, LXs have emerged as potential anti-fibrotic mediators that may influence pro-fibrotic cytokines and matrix-associated gene expression in response to growth factors. Here, we provide a review and an update of the biosynthesis, metabolism and bioactions of LXs and LX analogues, and the recent studies on their therapeutic potential as promoters of resolution and fibro-suppressants.

Figure 1

Representation of the temporal cellular and biochemical events in the onset and resolution of inflammation. The early phase of inflammation is characterized by the release of pro-inflammatory mediators and extravascular accumulation of neutrophils, followed by infiltration of monocytes that differentiate into macrophage. This phase is characterized by the formation of anti-inflammatory and pro-resolution mediators (LXs, resolvins). These mediators stop further neutrophil trafficking and facilitate the removal of apoptotic cells. The ingestion of apoptotic cells results in potent anti-inflammatory effects through the production of anti-inflammatory cytokines such as TGF-β1, IL-10 and PGE₂, and the decrease of release of pro-inflammatory mediators, including IL-8, TNF-α and TXA₂. This figure is adapted from Serhan et al. (2007). IL = interleukin; TNF-α= tumour necrosis factor-α; LTs = leukotrienes; Tx = thromboxane; GM-CSF = granulocyte–macrophage colony-stimulating factor; PGs = prostaglandins; ASA = aspirin; LXs = lipoxins; Rvs = resolvins; PDs = protectins; ATL = aspirin-triggered lipoxins; ATRv = aspirin-triggered resolvins; TGF-β= transforming growth factor β; VEGF = vascular endothelial growth factor; PAF = platelet-activating factor; PGE₂= prostaglandin E₂.

Figure 2

Structure of native lipoxins (LXs), 15-epi-LXs and synthetic analogues. The figure shows the structure of the native LXs (LXA₄ and LXB₄), aspirin-triggered LXs [aspirin-triggered lipoxin (ATL); 15-epi-LXA₄ and 15-epi LXB₄]. In order to increase the half-life of LXA₄, and ATL, analogues resistant to enzymatic conversion by ω-oxidation and PGDH were designed (e.g. 16-p-fluorophenoxy-15-epi-LXA₄ methyl ester) (Takano et al., 1998; Clish et al., 1999; Gewirtz et al., 1999; Karp et al., 2004). Modification of the tetraene structure to a trienyne further enhanced chemical stability as depicted here in the structure of the 3-oxa LX analogue ZK-142 and its 11-dehydro analogue ZK-994, which are topically and orally active anti-inflammatory agents (Guilford et al., 2004). More recently, a new class of lipoxin analogues featuring a benzo-fused ring system have been designed and proved to be as potent as native LXA₄ in a series of in vitro and in vivo studies (O'Sullivan et al., 2007; Petasis et al., 2008).

Figure 3

Lipoxin (LX) and receptors. The actions of LXs and aspirin-triggered lipoxins are mediated through several mechanisms. These include activation of high-affinity, LX-specific G-protein coupled receptor (ALXR), interaction of subclasses of cysteinyl peptide–LTs receptor. Direct activation of the lipoxin receptor results in anti-inflammatory and pro-resolution activities. Indirect inhibition, through other receptors such as CysLT and growth-factor receptors (such as vascular endothelial growth factor and platelet-derived growth factor receptors), reduces angiogenesis, and mesangial cell proliferation and fibrosis. Another potential receptor of LXA₄ is the nuclear receptor aryl hydrocarbon receptor, which triggers expression of suppressor of cytokine signalling 2 in LX-stimulated DC.

Figure 4

Target cells for lipoxin A₄ and aspirin-triggered lipoxin bioactions.

Figure 5

Phagocytosis of apoptotic cells by macrophages is augmented by ligands of the lipoxin (LX) receptor. LXs and other lipoxin A₄ receptor (ALXR) ligands (i.e. aspirin-triggered lipoxins and annexin-1) engage ALXR on the macrophages, leading to intracellular signalling events, including activation of the small GTPases RhoA, Rac and Cdc42; myosin assembly; and actin rearrangement, priming the macrophages for the phagocytosis of apoptotic cells. Following ingestion, the production of anti-inflammatory cytokines is increased, whereas the release of pro-inflammatory mediators is decreased as depicted in schematic. Images depict human monocyte-derived macrophages and apoptotic neutrophil (A); after stimulation with LXA₄ (1 nM), rearrangement of actin cytoskeleton is observed (B) and phagocytosis ensues (note two DAPI-stained nuclei in C).These conclusions are based on Maderna et al. (2002) and Reville et al. (2006).