Annexin‐A1: a pivotal regulator of the innate and adaptive immune systems

Abstract

The glucocorticoids are the most potent anti-inflammatory drugs that we possess and are effective in a wide variety of diseases. Although their action is known to involve receptor mediated changes in gene transcription, the exact mechanisms whereby these bring about their pleiotropic action in inflammation are yet to be totally understood. Whilst many different genes are regulated by the glucocorticoids, we have identified one particular protein-annexin A1 (Anx-A1)-whose synthesis and release is strongly regulated by the glucocorticoids in many cell types. The biology of this protein, as revealed by studies using transgenic animals, peptide mimetics and neutralizing antibodies, speaks to its role as a key modulator of both of the innate and adaptive immune systems. The mechanism whereby this protein exerts its effects is likely to be through the FPR receptor family-a hitherto rather enigmatic family of G protein coupled receptors, which are increasingly implicated in the regulation of many inflammatory processes. Here we review some of the key findings that have led up to the elucidation of this key pathway in inflammatory resolution.

Annexins – insights from knockout mice

“…AnxA1 was originally discovered in the late 1970s when aiming to identify factors that mediate the anti-inflammatory action of glucocorticoids (D'Acquisto et al, 2008;Gavins and Hickey, 2012). AnxA1 is found in most tissues with significant amounts commonly expressed in differentiated cell types, in particular macrophages and neutrophils, as well as cells from the nervous and endocrine system (Gerke et al, 2005;D'Acunto et al, 2014) ( Table 1).…”

“…How the interaction of AnxA1 with FPR2 translates into the multiple and diverse molecular events that drive immune response is not fully understood, but activation of mitogen-activated protein kinases (MAPK), including extracellular signal-regulated kinases 1/2 (Erk1/2) and p38MAPK, Akt, c-Jun N-terminal kinase, increase of intracellular Ca 2+ levels appear to be involved. Other contributing candidates include several chemokine receptors (Drechsler et al, 2015;Machado et al, 2016) and transcription factors (D'Acquisto et al, 2008;Perretti and D'Acquisto, 2009;Yang et al, 2013a).…”

“…Furthermore, AnxA1 downregulates the production of pro-inflammatory mediators including eicosanoids, nitric oxide, and several interleukins (ILs). More recently, AnxA1/FPR2 has also been linked to the adaptive immune response (D'Acquisto et al, 2008;Perretti and D'Acquisto, 2009;Gavins and Hickey, 2012;Yang et al, 2013a,b). However, a clear picture is still to emerge, as AnxA1 deficiency may have stimulatory or inhibitory effects on the adaptive immune system depending on the experimental settings and disease models analysed (D'Acquisto et al, 2008;Yang et al, 2013a,b).…”

“…To date, administration of the AnxA1 derived N-terminal Ac2-26 peptide is the most common approach (D'Acquisto et al, 2008;Perretti and D'Acquisto, 2009;Perretti and Dalli, 2009;Gavins and Hickey, 2012;Yang et al, 2013a;Locatelli et al, 2014;Sugimoto et al, 2016). Overall, exogenous administration of AnxA1 or AnxA1-derived peptides are effective to limit or resolve inflammation in a large range of disease models in rodents, including stroke, myocardial ischemia, non-alcoholic steatohepatitis, rheumatoid arthritis, multiple sclerosis, colitis and asthma.…”

Annexin A1 is a new functional linker between actin filaments and phagosomes during phagocytosis

“…Annexin A1, formerly known as lipocortin 1, was initially identified as an anti-inflammatory protein that is glucocorticoid regulated and secreted atypically from cells (D'Acquisto et al, 2008). Intracellularly, annexin A1 is predominantly a cytosolic…”