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

Table 1

In vitro and in vivo evidence for anti-inflammatory and proresolving properties of annexin A1 and its fragments.

Agent	Experimental model	Outcome/effect on resolution	References
Inhibition of neutrophil recruitment
AnxA1	Neutrophil/endothelial interaction (in vitro)	↓ PMN capture, rolling, and adhesion; ↓ PMN transmigration	[27, 48, 54, 55]
	Neutrophil/endothelial interaction (in vivo)	↓ PMN rolling, adhesion, and emigration; ↑ Detachment of adherent PMN	[27, 56]
	Human PMN	↑ L-selectin shedding	[57, 58]
	IL-1β inflamed air pouch	↓ PMN migration	[26, 59]
	Carrageenan-induced paw edema	↓ edema; ↓ leukocyte infiltration	[27]
SAnxA1	Neutrophil/endothelial interaction (in vitro)	↓ PMN capture, rolling, and adhesion	[27]
	Neutrophil/endothelial interaction (in vivo)	↓ PMN rolling and adhesion	[27]
	fMLP induced skin edema	↓ MPO activity	[27]
	Carrageenan-induced paw edema	↓ edema; ↓ leukocyte infiltration	[27]
AnxA1	Neutrophil/endothelial interaction (in vitro)	↓ PMN rolling and adhesion	[26]
	Neutrophil/endothelial interaction (in vivo)	↓ PMN adhesion	[26]
	IL-1β inflamed air pouch	↓ PMN recruitment	[26]
Ac2–26	Neutrophil/endothelial interaction (in vitro)	↓ PMN capture, rolling, and adhesion; ↑ L-selectin shedding	[40, 54]
	Human PMN activated with CCL5	↓ β integrin activation	[40]
	Neutrophil/endothelial interaction (in vivo)	↓ PMN adhesion and emigration; ↑ detachment of adherent PMN	[56]
Ac1–26	Neutrophil/endothelial interaction (in vitro)	↓ PMN transmigration	[48]
Ac9–25	Neutrophil/endothelial interaction (in vitro)	↓ PMN adhesion and transmigration; ↑ L-selectin shedding	[48]
AF-2	Neutrophil/endothelial interaction (in vitro)	↓ PMN adhesion; ↓ β2 integrin expression	[60, 61]
Induction of neutrophil apoptosis
AnxA1	Human PMN	↑ apoptosis (↓ pBAD)	[57]
AnxA1	Human neutrophils stimulated with SAA	↑ apoptosis	[26]
Ac2–26	Human neutrophils stimulated with SAA	↑ apoptosis; (↑ caspase-3 cleavage; JNK dependent)	[47]
	Acute pleurisy	↑ apoptosis; (↑ Bax; ↑ caspase-3 cleavage; ↓ Mcl-1; ↓ NF-κB; ↓ pERK)	[11]
	Skin allograft model	↑ skin allograft survival; ↑ apoptosis; ↓ neutrophil transmigration	[62]
Enhancement of monocyte recruitment and efferocytosis
Ac2–7	Transmigration assay (in vitro)	Stimulating human monocyte chemotaxis	[63]
AnxA1	Chemotaxis assays	Human monocyte chemoattractant	[64]
	Administration to mouse peritoneum	↑ monocyte recruitment	[64]
	Phagocytosis of apoptotic leukocytes	↑ efferocytosis; ↑ binding of apoptotic cells to MØ	[65, 66]
Ac2–26	Phagocytosis of apoptotic neutrophils	↑ phagocytosis; Inducing actin reorganization; ↑ TGF-β release; ↓ IL-8 release	[67]
AnxA1	Zymosan-induced peritonitis	↑ efferocytosis	[26]
Macrophage reprogramming
AnxA1	Human MØ cell line	Induced M2-like polarization	[44]
	Human monocytes	↑ IL-10	[47]
	LPS stimulated THP-1 MØ	↓ IL-6, TNF, and IL-1β	[66]
	MØ from NASH livers	↓ M1 polarization (↓ iNOS, IL-12p40); ↑ IL-10	[68]
	Intraperitoneal injection	↑ IL-10	[47]
	Phagocytosis of apoptotic neurons by microglial cells	↓ phagocytosis of healthy cells; ↓ NO production	[69]
Ac2–26	Endotoxin-challenged monocytes	↓ IL-6 signalling; ↓ TNF-α release	[70]

AnxA1: annexin A1; fMLP: N-Formyl-Met-Leu-Phe; IL: interleukin; MPO: Myeloperoxidase; MØ, macrophage; NASH; nonalcoholic steatohepatitis; PMN: polymorphonuclear; NO: nitric oxide; SAA: serum amyloid A; SAnxA1: SuperAnxA1 (proteinase-3 resistant); TGF-β: transforming growth factor-β; TNF-α: tumor necrosis factor alpha.