Lipid-Derived Mediators in Endogenous Anti-Inflammation and Resolution: Lipoxins and Aspirin-Triggered 15-epi-Lipoxins

It is well appreciated that lipid-derived mediators play key roles in inflammation and many other physiologic responses where multicellular processes are involved. Among them, lipoxins (LX) and aspirin-triggered LX (ATL) evoke actions of interest in a range of physiologic and pathophysiologic processes, and these two series have emerged as founding members of the first class of lipid/chemical mediators “switched on” in the resolution phase of an inflammatory reaction. These unique compounds possess a trihydroxytetraene structure and are both structurally and functionally distinct among the many groups of lipid-derived bioactive mediators. LXA4 and 15-epi-LXA(4) (a member of the ATL series) display leukocyte-selective actions that enable them to serve as endogenous “stop signals” in multicellular events in that they modulate adherence, transmigration, and chemotaxis. Both LXA(4) and 15-epi-LXA(4) elicit these responses via a G protein-coupled receptor (GPCR), termed ALXR, identified in human and murine tissues. Among eicosanoids, ALXR is stereoselective for LXA(4) (5S,6R,15S-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid). Its aspirin-triggered 15R epimer (15-epi-LXA(4)) and their bioactive stable analogs act in the subnanomolar to nanomolar range in human cellular systems and murine models of acute inflammation and reperfusion. ALXR also has the ability to interact with a wide panel of small peptides that give different signaling responses in vitro than LXA(4) or its analogs, suggesting that ALXR is capable of serving as a multirecognition receptor in immune responses. Characterization of ALXR and development of metabolically stable LX and ATL analogs that are mimetics rapidly advanced our appreciation of the mechanism of LX actions and the potential utility of these counter-regulatory biocircuits in the quest to control local inflammatory events. In this on-line update, LX and ATL biosynthesis and the LXA(4) specific receptor, termed ALXR, are reviewed with a focus on their roles in inflammation and resolution with respect to pharmacology, molecular biology, and signal transduction in several cell types and animal models investigated thus far.