Annexin 1: More than an anti-phospholipase protein

Department of Pharmaceutical Sciences, University of Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy.
Inflammation Research (Impact Factor: 2.14). 05/2004; 53(4):125-32. DOI: 10.1007/s00011-003-1235-z
Source: PubMed

ABSTRACT Annexin 1 (ANXA1) is the first characterized member of the annexin family of proteins able to bind (i.e. to annex) to cellular membranes in a calcium-dependent manner. ANXA1 may be induced by glucocorticoids in inflammatory cells and shares with these drugs many anti-inflammatory effects. Originally described as a phospholipase A2 (PLA2)-inhibitory protein, ANXA1 can affect many components of the inflammatory reaction besides the metabolism of arachidonic acid. Recent data have shown that ANXA1 may specifically target cytosolic PLA2 by both direct enzyme inhibition and suppression of cytokine-induced activation of the enzyme. ANXA1 inhibits the expression and/or activity of other inflammatory enzymes like inducible nitric oxide synthase (iNOS) in macrophages and inducible cyclooxygenase (COX-2) in activated microglia. The inhibition of iNOS expression may be caused by the stimulation of IL-10 release induced by ANXA1 in macrophages. Like glucocorticoids, ANXA1 exerts profound inhibitory effects on both neutrophil and monocyte migration in inflammation. Several mechanisms may contribute to the protein effect on cell migration, namely the activation of receptors like the formyl peptide receptor (FPR) and the lipoxin A4 receptor (ALXR), the shedding of L-selectin, the binding to alpha4beta1 integrin and carboxylated N-glycans. Furthermore, again mimicking the action of glucocorticoids, ANXA1 promotes inflammatory cell apoptosis associated with transient rise in intracellular calcium and caspase-3 activation. Finally, ANXA1 has been recently identified as one of the 'eat-me' signals on apoptotic cells to be recognised and ingested by phagocytes. Thus, ANXA1 may contribute to the anti-inflammatory signalling that allows safe post-apoptotic clearance of dead cells.

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Available from: Egle Solito, Aug 12, 2015
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    • "Annexin A1 (AnxA1), originally reported as a calcium and phospholipid binding protein induced by glucocorticoids, is an endogenous anti-inflammatory mediator. The antiinflammatory effects of AnxA1 have been documented in vivo and in vitro, and include inhibition of leukocyte recruitment, inhibition of pro-inflammatory cytokine expression, inhibition of phospholipase A2 activity and induction of apoptosis (Lim et al., 2007; Parente et al., 2004; Perretti et al., 2009). A role for AnxA1 in the regulation of inflammatory arthritis has been supported by several studies. "
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    ABSTRACT: Background and purposeAnnexin A1 (AnxA1) is an endogenous anti-inflammatory molecule that binds to the formyl-peptide receptor 2 (FPR2). However, the potential for therapeutic FPR ligands to modify immune-mediated disease has been little explored. We investigated the effects of a synthetic FPR ligand on joint disease in the K/BxN model of RA and RA fibroblast-like synoviocytes (FLS).Experimental approachArthritis was induced by injection of K/BxN serum at day 0 and 2 in wild-type or AnxA1-/- mice, and clinical and histopathologic manifestations measured. WT mice were treated with the FPR agonist compound 43 (Cpd43) (6 or 30 mg/kg). Effects of AnxA1 and Cpd43 were also assessed in RANKL- induced osteoclastogenesis in RAW 264.7 cells, and in human RA FLS and macrophages.Key resultsTreatment with Cpd43 before or after the onset of arthritis significantly reduced clinical disease severity and attenuated synovial TNF-α and osteoclast-associated gene expression. Conversely, deficiency of AnxA1 in mice exacerbated arthritis severity in the K/BxN model. In vitro, Cpd43 suppressed osteoclastogenesis and NFAT activity elicited by RANKL, and inhibited IL-6 secretion by mouse macrophages. In human RA joint-derived FLS and monocyte-derived macrophages, Cpd43 treatment also inhibited IL-6 release, while blocking FPR2 or silencing AnxA1 had the reverse effect.Conclusions and ImplicationsThese data demonstrate that the FPR agonist Cpd43 reduces osteoclastogenesis and inflammation in a mouse model of RA and exhibited anti-inflammatory effects in relevant human cells. These data suggest that FPR ligands may represent novel therapeutic agents with which to ameliorate inflammation and bone damage in RA.
    British Journal of Pharmacology 05/2014; 171(17). DOI:10.1111/bph.12768 · 4.99 Impact Factor
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    • "A recent paper using AnxA1 knockout mice has demonstrated that expression of AnxA1 by resident bone marrow macrophages is required for the efficient phagocytosis of apoptotic neutrophils under homeostatic conditions in vivo (Dalli et al., 2012). In the context of neutrophil apoptosis, it has been shown that AnxA1 regulates leukocyte apoptosis not only in vitro (Solito et al., 2003; Parente & Solito, 2004) but also in vivo under inflammatory settings (Vago et al., 2012). Collectively, we can propose that during ongoing inflammation, endogenous and exogenous AnxA1 can exert exquisite modulation on the fate of recruited neutrophils by promoting their death by apoptosis, as well as their safe removal by phagocytes (efferocytosis), dampens inflammatory mediators and promotes monocyte subendothelial space locomotion. "
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    ABSTRACT: Inflammation is a beneficial host reaction to tissue damage and has the essential primary purpose of restoring tissue homeostasis. Inflammation plays a major role in containing and resolving infection and may also occur under sterile conditions. The cardinal signs of inflammation dolor, calor, tumor and rubor are intrinsically associated with events including vasodilatation, edema and leukocyte trafficking into the site of inflammation. If uncontrolled or unresolved, inflammation itself can lead to further tissue damage and give rise to chronic inflammatory diseases and autoimmunity with eventual loss of organ function. It is now evident that the resolution of inflammation is an active continuous process that occurs during an acute inflammatory episode. Successful resolution requires activation of endogenous programs with switch from production of pro-inflammatory towards pro-resolving molecules, such as specific lipid mediators and annexin A1, and the non-phlogistic elimination of granulocytes by apoptosis with subsequent removal by surrounding macrophages. These processes ensure rapid restoration of tissue homeostasis. Here, we review recent advances in the understanding of resolution of inflammation, highlighting the pharmacological strategies that may interfere with the molecular pathways which control leukocyte survival and clearance. Such strategies have proved beneficial in several pre-clinical models of inflammatory diseases, suggesting that pharmacological modulation of the resolution process may be useful for the treatment of chronic inflammatory diseases in humans.
    Pharmacology [?] Therapeutics 04/2013; 139(13). DOI:10.1016/j.pharmthera.2013.04.006 · 7.75 Impact Factor
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    • "During the inflammatory response, AnxA1 is translocated from the cell cytoplasm to the membrane, resulting in a decrease in the transmigration of inflammatory cells to the site of injury [9]. Furthermore, AnxA1 plays its antiinflammatory role by inhibiting the activities of phospholipase A2 and inducible nitric oxide synthase [10]. It is also associated with modifications of the cytoskeleton, transport of molecules, ion flux, differentiation and migration, cell growth, and apoptosis [11]. "
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    ABSTRACT: Objective. The anti-inflammatory proteins annexin-A1 and galectin-1 have been associated with tumor progression. This scenario prompted us to investigate the relationship between the gene and protein expression of annexin-A1 (ANXA1/AnxA1) and galectin-1 (LGALS1/Gal-1) in an inflammatory gastric lesion as chronic gastritis (CG) and gastric adenocarcinoma (GA) and its association with H. pylori infection. Methods. We analyzed 40 samples of CG, 20 of GA, and 10 of normal mucosa (C) by the quantitative real-time PCR (qPCR) technique and the immunohistochemistry assay. Results. High ANXA1 mRNA expression levels were observed in 90% (36/40) of CG cases (mean relative quantification RQ = 4.26 ± 2.03) and in 80% (16/20) of GA cases (mean RQ = 4.38 ± 4.77). However, LGALS1 mRNA levels were high (mean RQ = 2.44 ± 3.26) in 60% (12/20) of the GA cases, while low expression was found in CG (mean RQ = 0.43 ± 3.13; P < 0.01). Normal mucosa showed modest immunoreactivity in stroma but not in epithelium, while stroma and epithelium displayed an intense immunostaining in CG and GA for both proteins. Conclusion. These results have provided evidence that galectin-1 and mainly annexin-A1 are overexpressed in both gastritis and gastric cancer, suggesting a strong association of these proteins with chronic gastric inflammation and carcinogenesis.
    Mediators of Inflammation 01/2013; 2013:152860. DOI:10.1155/2013/152860 · 3.24 Impact Factor
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