Annexin A1 and the Resolution of Inflammation: Modulation of Neutrophil Recruitment, Apoptosis, and Clearance

Figure 1

Cellular events associated with the anti-inflammatory and proresolving effects of annexin A1 (AnxA1) and its mimetic N-terminal peptides. AnxA1 modulates a wide range of cellular and molecular steps of the inflammatory response and is deeply involved in the endogenous mechanisms that are activated to bring about proper resolution. Pharmacological administration of AnxA1 results in decreased neutrophil rolling (1) and adhesion (2) to endothelium, increased detachment of adherent cells (3), and inhibition of neutrophil transmigration (4). In addition, AnxA1 is able to induce apoptosis, overriding the prosurvival signals that cause prolonged lifespan of neutrophils at the inflammatory site (6). Endogenous and exogenous AnxA1 also promote monocyte recruitment (5) and clearance of apoptotic neutrophils by macrophages (7). Phagocytosis of apoptotic neutrophils by macrophages is coupled with release of anti-inflammatory signals, including transforming growth factor-β, and lower levels of proinflammatory cytokines (8). Besides, AnxA1 is related to macrophage reprogramming toward a proresolving phenotype (8). Initial in vitro studies using AnxA1 knock-down leucocytes demonstrate that AnxA1 prevents proinflammatory cytokine production after phagocytosis of secondary necrotic cells. This effect provides an important fail-safe mechanism counteracting inflammatory responses when the timely clearance of apoptotic cells has failed (9).