Biasing the lipoxin A 4 /formyl peptide receptor 2 pushes inflammatory resolution

Abstract

Acute inflammation is an innate host-defense mechanism against invading pathogens and tissue injury. Neutralization of the offending insult ideally prompts resolution of inflammation and restoration of tissue homeostasis. Resolution of inflammation is an active process governed by resolution programs (1), involving a novel group of lipid and protein mediators, which possess dual anti-inflammatory and proresolution properties (2). Excessive inflammation or failure of the initial inflammatory response to resolve in a timely manner results in nonresolving inflammation and persisting tissue damage, which are now considered as critical components of many chronic human diseases (3). Intriguingly, many pro- and anti-inflammatory signals and proresolving circuits converge on select receptors, which integrate contrasting cues to determine the course of inflammation. Among these receptors is ALX/FPR2 (lipoxin A4 receptor or formyl peptide receptor 2; hereafter referred to as ALX), which binds both protein and lipid ligands that evoke opposing biological responses (4, 5). At present, little is known about the molecular basis for such diverse actions. In PNAS, Cooray et al. (6) present another advance in understanding signaling through the ALX receptor. Using coimmunoprecipitation and bioluminescence resonance energy transfer (BRET) assays in transfected cells combined with functional assays in leukocytes and in vivo, the authors provide important insights into how ligand-biased activation and conformational change in ALX shape opposing biological functions.