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: 2.35). 05/2004; 53(4):125-32. DOI: 10.1007/s00011-003-1235-z
Source: PubMed


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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    • "During the initial steps of acute inflammation, AnxA1 limits the recruitment of leukocytes and the production of proinflammatory mediators [80]. During the resolution phase, AnxA1 acts by inducing the apoptosis of neutrophils and this effect is associated with increased expression of cleaved caspase-3 and BAX and decreased expression of pERK1/2, NF-κB, and MCL-1 [21, 81–83] and increasing efferocytosis by macrophages [83–85]. Interestingly, activation of FPR2 by AnxA1 and LXA4 skewed M1 macrophages to M2-like cells [86]. "
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    ABSTRACT: Inflammation is a physiological response of the immune system to injury or infection but may become chronic. In general, inflammation is self-limiting and resolves by activating a termination program named resolution of inflammation. It has been argued that unresolved inflammation may be the basis of a variety of chronic inflammatory diseases. Resolution of inflammation is an active process that is fine-tuned by the production of proresolving mediators and the shutdown of intracellular signaling molecules associated with cytokine production and leukocyte survival. Apoptosis of leukocytes (especially granulocytes) is a key element in the resolution of inflammation and several signaling molecules are thought to be involved in this process. Here, we explore key signaling molecules and some mediators that are crucial regulators of leukocyte survival in vivo and that may be targeted for therapeutic purposes in the context of chronic inflammatory diseases.
    Mediators of Inflammation 07/2014; 2014(3):829851. DOI:10.1155/2014/829851 · 3.24 Impact Factor
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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 purpose: Annexin A1 (AnxA1) is an endogenous anti-inflammatory protein and agonist of 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 agonist on joint disease in the K/BxN model of rheumatoid arthritis (RA) and RA fibroblast-like synoviocytes (FLS). Experimental approach: Arthritis was induced by injection of K/BxN serum at day 0 and 2 in wild-type (WT) or AnxA1(-/-) mice and clinical and histopathological manifestations measured 8-11 days later. WT mice were given the FPR agonist compound 43 (Cpd43) (6 or 30 mg·kg(-1) i.p.) for 4 days. Effects of AnxA1 and Cpd43 on RANKL-induced osteoclastogenesis were assessed in RAW 264.7 cells and human RA FLS and macrophages. Key results: Treatment with Cpd43 before or after the onset of arthritis reduced clinical disease severity and attenuated synovial TNF-α and osteoclast-associated gene expression. Deletion 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 inhibited IL-6 release, while blocking FPR2 or silencing AnxA1 increased this release. Conclusions and implications: The FPR agonist Cpd43 reduced 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 capable of ameliorating inflammation and bone damage in RA.
    British Journal of Pharmacology 05/2014; 171(17). DOI:10.1111/bph.12768 · 4.84 Impact Factor
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    • "Some studies suggest that ANXA1 demonstrated an antiproliferative activity in lymphocytes [17,19,44,47]. It was demonstrated a reduction in ANXA1 expression in CD4+ and CD8+ T cells. "
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    ABSTRACT: Malaria is the most prevalent parasitic disease in the world. In Brazil, the largest number of malaria cases (98%) is within the Legal Amazon region, where Plasmodium vivax is responsible for over 80% of diagnosed cases. The aim of this study was to investigate the annexin-A1 expression in CD4+, CD8+ T cells, regulatory T cells (Treg) and cytokine IL-10 quantification in plasma from patients with malaria caused by P. vivax. The quantification of the cytokine IL-10 of patients infected with P. vivax and healthy controls were evaluated by enzyme-linked immunosorbent assay (ELISA). The determination of the expression of annexin-A1 in lymphocytes from patients and healthy controls was determined by immunofluorescence staining. All results were correlated with the parasitaemia and the number of previous episodes of malaria. The cytokine IL-10 plasma levels showed a significant increase in both patients with low (650.4 +/- 59.3 pg/mL) and high (2870 +/- 185.3 pg/mL) parasitaemia compared to the control (326.1 +/- 40.1 pg/mL). In addition, there was an increase of this cytokine in an episode dependent manner (individuals with no previous episodes of malaria - primoinfected: 363.9 +/- 31.1 pg/mL; individuals with prior exposure: 659.9 +/- 49.4 pg/mL). The quantification of annexin-A1 expression indicated a decrease in CD4+ and CD8+ T cells and an increase in Treg in comparison with the control group. When annexin-A1 expression was compared according to the number of previous episodes of malaria, patients who have been exposed more than once to the parasite was found to have higher levels of CD4+ T cells (96.0 +/- 2.5 A.U) compared to primoinfected (50.3 +/- 1.7). However, this endogenous protein had higher levels in CD8+ (108.5 +/- 3.1) and Treg (87.5 +/- 2.5) from patients primoinfected. This study demonstrates that in the patients infected with P. vivax the release of immunoregulatory molecules can be influenced by the parasitaemia level and the number of previous episodes of malaria. annexin-A1 is expressed differently in lymphocyte sub-populations and may have a role in cell proliferation. Furthermore, annexin-A1 may be contributing to IL-10 release in plasma of patients with vivax malaria.
    Malaria Journal 12/2013; 12(1):455. DOI:10.1186/1475-2875-12-455 · 3.11 Impact Factor
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