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Review
. 2016:2016:8239258.
doi: 10.1155/2016/8239258. Epub 2016 Jan 13.

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

Michelle Amantéa Sugimoto  1 , Juliana Priscila Vago  2 , Mauro Martins Teixeira  3 , Lirlândia Pires Sousa  4
Affiliations
Review

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

Michelle Amantéa Sugimoto et al. J Immunol Res. 2016.

Abstract

Neutrophils (also named polymorphonuclear leukocytes or PMN) are essential components of the immune system, rapidly recruited to sites of inflammation, providing the first line of defense against invading pathogens. Since neutrophils can also cause tissue damage, their fine-tuned regulation at the inflammatory site is required for proper resolution of inflammation. Annexin A1 (AnxA1), also known as lipocortin-1, is an endogenous glucocorticoid-regulated protein, which is able to counterregulate the inflammatory events restoring homeostasis. AnxA1 and its mimetic peptides inhibit neutrophil tissue accumulation by reducing leukocyte infiltration and activating neutrophil apoptosis. AnxA1 also promotes monocyte recruitment and clearance of apoptotic leukocytes by macrophages. More recently, some evidence has suggested the ability of AnxA1 to induce macrophage reprogramming toward a resolving phenotype, resulting in reduced production of proinflammatory cytokines and increased release of immunosuppressive and proresolving molecules. The combination of these mechanisms results in an effective resolution of inflammation, pointing to AnxA1 as a promising tool for the development of new therapeutic strategies to treat inflammatory diseases.

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Figures

Figure 1
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).
Figure 2
Figure 2
Effect of exogenous administration of AnxA1 derived peptide Ac2–26 on LPS-induced pleurisy. Mice were injected with LPS (250 ng/cavity, i.pl.) and 4 h later received an injection of Ac2–26 (100 μg/mouse, i.pl. or i.p.). The treatment with the pan-caspase inhibitor zVAD-fmk (1 mg/kg, i.p.) was performed 15 min before the injection of peptide. The numbers of neutrophils (a) and mononuclear cells (b) were evaluated 20 h after drug treatment. Cells with distinctive apoptotic morphology (c and e) and Western blot for detection of cleaved caspase-3, Bax, Mcl-1, P-ERK, and P-IκB-α (d) were evaluated 4 h after the peptide treatment. ∗ P < 0.05 or ∗∗∗ P < 0.001 when compared with PBS-injected mice and # P < 0.05 or ## P < 0.01 when compared with vehicle-treated, LPS-injected mice. (e) Representative figures of nonapoptotic (asterisk) and apoptotic (arrows) neutrophils and apoptotic cells inside macrophages (arrowheads). PBS and vehicle (upper panels) and Ac2–26-treated (lower panels) animals are shown. Original data from Vago et al., 2012 [11].
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