Exploiting the Annexin A1 pathway for the development of novel anti-inflammatory therapeutics

Abstract

The appreciation that the inflammatory reaction does not 'spontaneously' finish, but rather that inflammatory resolution is an active phenomenon brought about by endogenous anti-inflammatory agonists opens multiple opportunities for a reassessment of the complexity of inflammation and its main mediators. This review dwells on one of these pathways, the one centred around the glucocorticoid-regulated protein Annexin A1 and its G protein-coupled receptor. In recent years, much of the knowledge detailing the processes by which Annexin A1 expresses its anti-inflammatory role on innate immunity has been produced. Moreover, the generation of the Annexin A1 null mouse colony has provided important proof-of-concept experiments demonstrating the inhibitory properties of this mediator in the context of inflammatory and/or tissue-injury models. Therefore, Annexin A1 acts as a pivotal homeostatic mediator, where if absent, inflammation would overshoot and be prolonged. This new understanding scientific information could guide us onto the exploitation of the biological properties of Annexin A1 and its receptor to instigate novel drug discovery programmes for anti-inflammatory therapeutics. This line of research relies on the assumption that anti-inflammatory drugs designed upon endogenous anti-inflammatory mediators would be burdened by a lower degree of secondary effects as these agonists would be mimicking specific pathways activated in our body for safe disposal of inflammation. We believe that the next few years will produce examples of such new drugs and the validity of this speculation could then be assessed.

Figure 1

Schematic representation of the required balance between pro- and anti-inflammatory mediators and pathways. (A) An equilibrium between pro-inflammatory mediators and effectors of anti-inflammation is required to assure a prompt yet spatially and temporally restricted inflammatory reaction. This is required for a proper function of the inflammatory response the host mounts upon infection and encounter with xenobiotics, so that upon killing and/or disposal of the inflammogen, resolution of inflammation is completed with restoring of tissue physiology and homeostasis regain. (B and C) Pro-inflammation in association with a deficient endogenous anti-inflammatory response, hence with inadequate resolution phase, would lead to disease; the same holds true if an inappropriate pro-inflammatory is produced, so that resolution of inflammation would prevail (e.g. leukocyte adhesion deficiency, whereby lack of leukocyte trafficking is at the basis of patients' inability to fight infections, leading to a poor life expectancy). Acceptance of this important yin/yan in inflammation ensues that chronic inflammatory disease (various forms of arthritis, vasculitis, psoriasis but also perhaps atherosclerosis and reperfusion injury conditions) could be due, at least partly, to an insufficient activation of the endogenous anti-inflammatory response so that resolution pathways are not properly activated and/or operating. Along this line, potentiation of one or more endogenous pro-resolving pathways could be another approach to the therapeutic control of inflammatory diseases.