Corrigendum to "Activation of Melanocortin Receptors MC1 and MC5 Attenuates Retinal Damage in Experimental Diabetic Retinopathy".

[This corrects the article DOI: 10.1155/2016/7368389.].

Activation of Melanocortin Receptors MC 1 and MC 5 Attenuates Retinal Damage in Experimental Diabetic Retinopathy.

We hypothesize that melanocortin receptors (MC) could activate tissue protective circuit in a model of streptozotocin- (STZ-) induced diabetic retinopathy (DR) in mice. At 12-16 weeks after diabetes induction, fluorescein angiography (FAG) revealed an approximate incidence of 80% microvascular changes, typical of DR, in the animals, without signs of vascular leakage. Occludin progressively decreased in the retina of mice developing retinopathy. qPCR of murine retina revealed expression of two MC receptors, Mc1r and Mc5r. The intravitreal injection (5 µL) of the selective MC1 small molecule agonist BMS-470539 (33 µmol) and the MC5 peptidomimetic agonist PG-901 (7.32 nM) elicited significant protection with regular course and caliber of retinal vessels, as quantified at weeks 12 and 16 after diabetes induction. Mouse retina homogenate settings indicated an augmented release of IL-1α, IL-1ß, IL-6, MIP-1α, MIP-2α, MIP-3α, and VEGF from diabetic compared to nondiabetic mice. Application of PG20N or AGRP and MC5 and MC1 antagonist, respectively, augmented the release of cytokines, while the agonists BMS-470539 and PG-901 almost restored normal pattern of these mediators back to nondiabetic values. Similar changes were quantified with respect to Ki-67 staining. Finally, application of MC3-MC4 agonist/antagonists resulted to be inactive with respect to all parameters under assessment.

The role of the Annexin-A1/FPR2 system in the regulation of mast cell degranulation provoked by compound 48/80 and in the inhibitory action of nedocromil.

1.We investigated the role of Annexin (ANX)-A1 and its receptor, ALX/FPR2, in the regulation of mast cell degranulation produced by compound 48/80. 2.Both human cord-blood derived mast cells (CBDMCs) and murine bone marrow derived mast cells (BMDMCs) release phosphorylated ANX-A1 during treatment with glucocorticoids or the mast cell 'stabilising' drugs ketotifen and nedocromil. 3.Compound 48/80 also stimulated ANX-A1 phosphorylation and release and this was also potentiated by nedocromil. Anti-ANX-A1 neutralising monoclonal antibodies (Mabs) enhanced the release of pro-inflammatory mediators in response to compound 48/80. 4.Nedocromil and ketotifen potently inhibited the release of histamine, PGD2, tryptase and ß-hexosaminidase from mast cells challenged with compound 48/80. Anti-ANX-A1 neutralising Mabs prevented the inhibitory effect of these drugs. 5.BMDMCs derived from Anx-A1−/− mice were insensitive to the inhibitory effects of nedocromil or ketotifen but cells retained their sensitivity to the inhibitory action of hu-r-ANX-A1. 6.The fpr2/3 antagonist WRW4 blocked the action of nedocromil on PGD2, but not histamine, release. BMDMCs derived from fpr2/3−/− mice were insensitive to the inhibitory effects of nedocromil on PGD2, but not histamine release. 7.Compound 48/80 stimulated both p38 and JNK phosphorylation in CBDMCs and this was inhibited by nedocromil. Inhibition of p38 phosphorylation was ANX-A1 dependent. 8.We conclude that ANX-A1 is an important regulator of mast cell reactivity to compound 48/80 exerting a negative feedback effect through a mechanism that depends at least partly on the FPR receptor.

Annexin A1 mimetic peptide controls the inflammatory and fibrotic effects of silica particles in mice.

BACKGROUND AND PURPOSE: Endogenous glucocorticoids are pro-resolving mediators, an example of which is the endogenous glucocorticoid-regulated protein annexin A1 (ANXA1). Because silicosis is an occupational lung disease characterized by unabated inflammation and fibrosis, in this study we tested the therapeutic properties of the N-terminal ANXA1-derived peptide annexin 1-(2-26) (Ac2-26) on experimental silicosis. EXPERIMENTAL APPROACH: Swiss-Webster mice were administered silica particles intranasally and were subsequently treated with intranasal peptide Ac2-26 (200 µg per mouse) or dexamethasone (25 µg per mouse) for 7 days, starting 6 h post-challenge. Ac2-26 abolished the leukocyte infiltration, collagen deposition, granuloma formation and generation of pro-inflammatory cytokines evoked by silica; these variables were only partially inhibited by dexamethasone. KEY RESULTS: A clear exacerbation of the silica-induced pathological changes was observed in ANXA1 knockout mice as compared with their wild-type (WT) littermate controls. Incubation of lung fibroblasts from WT mice with Ac2-26 in vitro reduced IL-13 or TGF-ß-induced production of CCL2 (MCP-1) and collagen, but this peptide did not affect the production of CCL2 (MCP-1) by stimulated fibroblasts from formyl peptide receptor type 1 (FPR1) knockout mice. Ac2-26 also inhibited the production of CCL2 (MCP-1) from fibroblasts of FPR2 knockout mice. CONCLUSIONS AND IMPLICATIONS: Collectively, our findings reveal novel protective properties of the ANXA1 derived peptide Ac2-26 on the inflammatory and fibrotic responses induced by silica, and suggest that ANXA1 mimetic agents might be a promising strategy as innovative anti-fibrotic approaches for the treatment of silicosis.

Protective effects of n-6 fatty acids-enriched diet on intestinal ischaemia/reperfusion injury involve lipoxin A4 and its receptor.

BACKGROUND AND PURPOSE: Long-term intake of dietary fatty acids is known to predispose to chronic inflammation, but their effects on acute intestinal ischaemia/reperfusion (I/R) injury is unknown. The aim of this study was to determine the consequences of a diet rich in n-3 or n-6 polyunsaturated fatty acids (PUFA) on intestinal I/R-induced damage. EXPERIMENTAL APPROACH: Mice were fed three different isocaloric diets: a balanced diet used as a control and two different PUFA-enriched diets, providing either high levels of n-3 or of n-6 PUFA. Intestinal injury was evaluated after intestinal I/R. PUFA metabolites were quantitated in intestinal tissues by LC-MS/MS. KEY RESULTS: In control diet-fed mice, intestinal I/R caused inflammation and increased COX and lipoxygenase-derived metabolites compared with sham-operated animals. Lipoxin A4 (LxA4 ) was significantly and selectively increased after ischaemia. Animals fed a high n-3 diet did not display a different inflammatory profile following intestinal I/R compared with control diet-fed animals. In contrast, intestinal inflammation was decreased in the I/R group fed with high n-6 diet and level of LxA4 was increased post-ischaemia compared with control diet-fed mice. Blockade of the LxA4 receptor (Fpr2), prevented the anti-inflammatory effects associated with the n-6 rich diet. CONCLUSIONS AND IMPLICATIONS: This study indicates that high levels of dietary n-6, but not n-3, PUFAs provides significant protection against intestinal I/R-induced damage and demonstrates that the endogenous production of LxA4 can be influenced by diet.

Cell surface-expressed phosphatidylserine as therapeutic target to enhance phagocytosis of apoptotic cells.

Impaired efferocytosis has been shown to be associated with, and even to contribute to progression of, chronic inflammatory diseases such as atherosclerosis. Enhancing efferocytosis has been proposed as strategy to treat diseases involving inflammation. Here we present the strategy to increase 'eat me' signals on the surface of apoptotic cells by targeting cell surface-expressed phosphatidylserine (PS) with a variant of annexin A5 (Arg-Gly-Asp-annexin A5, RGD-anxA5) that has gained the function to interact with α(v)ß(3) receptors of the phagocyte. We describe design and characterization of RGD-anxA5 and show that introduction of RGD transforms anxA5 from an inhibitor into a stimulator of efferocytosis. RGD-anxA5 enhances engulfment of apoptotic cells by phorbol-12-myristate-13-acetate-stimulated THP-1 (human acute monocytic leukemia cell line) cells in vitro and resident peritoneal mouse macrophages in vivo. In addition, RGD-anxA5 augments secretion of interleukin-10 during efferocytosis in vivo, thereby possibly adding to an anti-inflammatory environment. We conclude that targeting cell surface-expressed PS is an attractive strategy for treatment of inflammatory diseases and that the rationally designed RGD-anxA5 is a promising therapeutic agent.

Gene expression signature-based approach identifies a pro-resolving mechanism of action for histone deacetylase inhibitors.

Despite several therapies being currently available to treat inflammatory diseases, new drugs to treat chronic conditions with less side effects and lower production costs are still needed. An innovative approach to drug discovery, the Connectivity Map (CMap), shows how integrating genome-wide gene expression data of drugs and diseases can accelerate this process. Comparison of genome-wide gene expression data generated with annexin A1 (AnxA1) with the CMap revealed significant alignment with gene profiles elicited by histone deacetylase inhibitors (HDACIs), what made us to hypothesize that AnxA1 might mediate the anti-inflammatory actions of HDACIs. Addition of HDACIs (valproic acid, sodium butyrate and thricostatin A) to mouse macrophages caused externalization of AnxA1 with concomitant inhibition of cytokine gene expression and release, events that occurred independently as this inhibition was retained in AnxA1 null macrophages. In contrast, novel AnxA1-mediated functions for HDACIs could be unveiled, including promotion of neutrophil apoptosis and macrophage phagocytosis, both steps crucial for effective resolution of inflammation. In a model of acute resolving inflammation, administration of valproic acid and sodium butyrate to mice at the peak of disease accelerated resolution processes in wild type, but much more modestly in AnxA1 null mice. Deeper analyses revealed a role for endogenous AnxA1 in the induction of neutrophil death in vivo by HDACIs. In summary, interrogation of the CMap revealed an unexpected association between HDACIs and AnxA1 that translated in mechanistic findings with particular impact on the processes that regulate the resolution of inflammation. We propose non-genomic modulation of AnxA1 in immune cells as a novel mechanism of action for HDACIs, which may underlie their reported efficacy in models of chronic inflammatory pathologies.

High density micromass cultures of a human chondrocyte cell line: a reliable assay system to reveal the modulatory functions of pharmacological agents.

Osteoarthritis is a highly prevalent and disabling disease for which we do not have a cure. The identification of suitable molecular targets is hindered by the lack of standardized, reproducible and convenient screening assays. Following extensive comparisons of a number of chondrocytic cell lines, culture conditions, and readouts, we have optimized an assay utilizing C-28/I2, a chondrocytic cell line cultured in high-density micromasses. Utilizing molecules with known effects on cartilage (e.g. IL-1ß, TGFß1, BMP-2), we have exploited this improved protocol to (i) evoke responses characteristic of primary chondrocytes; (ii) assess the pharmacodynamics of gene over-expression using non-viral expression vectors; (iii) establish the response profiles of known pharmacological treatments; and (iv) investigate their mechanisms of action. These data indicate that we have established a medium-throughput methodology for studying chondrocyte-specific cellular and molecular responses (from gene expression to rapid quantitative measurement of sulfated glycosaminoglycans by Alcian blue staining) that may enable the discovery of novel therapeutics for pharmacological modulation of chondrocyte activation in osteoarthritis.

Microvascular thrombosis and CD40/CD40L signaling.

BACKGROUND: Although inflammation and thrombosis are now recognized to be interdependent processes that activate and perpetuate each other, the signaling molecules that link these two processes remain poorly understood. OBJECTIVES: The objective of this study was to assess the contribution of the CD40/CD40L signaling system to the enhanced microvascular thrombosis that accompanies two distinct experimental models of inflammation, that is, endotoxemia (lipopolysaccharide [LPS]) and dextran sodium sulfate (DSS)-induced colitis. METHODS: Thrombosis was induced in cerebral (LPS model) and cremaster muscle (DSS model) arterioles and venules of wild-type (WT) mice and mice deficient in either CD40 (CD40(-/-)) or CD40L (CD40L(-/-)), using the light/dye (photoactivation) method. RESULTS AND CONCLUSIONS: A comparison of thrombus formation between WT and mutant mice revealed a role for CD40 and/or CD40L in the inflammation-enhanced thrombosis responses in both of the cerebral and muscle vasculatures. However, the relative contributions of CD40 and its ligand to thrombus formation differed between vascular beds (brain vs. muscle) and vessel types (arterioles vs. venules). The protective effect of CD40L deficiency in cerebral arterioles exposed to LPS was significantly blunted by administration of soluble CD40L. These findings implicate CD40 and its ligand in the enhanced thrombus formation that is associated with acute and chronic inflammation.

Cross-talk between minimally primed HL-60 cells and resting HUVEC reveals a crucial role for adhesion over extracellularly released oxidants.

This study demonstrates that a long-lasting co-culture of neutrophil surrogates (HL-60 cells), minimally primed by platelet activating factor (PAF), and resting endothelial cells (EC) results in the elaboration of an hyper-adhesive endothelial surface, as measured by the increase in the expression of endothelial adhesion molecules E-Selectin, VCAM-1, and ICAM-1. This endothelial dysfunction is mediated by the activation of the redox-sensitive transcription factor NF-κB through an exclusive adhesion-driven mechanism active in the endothelial cell: reactive oxygen and nitrogen species, extracellularly released by minimally primed HL-60 cells, are not involved in the induction of the endothelial dysfunction. By exploring for the first time the potential for minimally primed neutrophil surrogates to induce endothelial dysfunction, this study suggests a novel mechanism which may be operative in pathologies, mediated by minimally primed neutrophils, such as hyperdyslipidemia and cardiovascular complications.

The melanocortin MC(1) receptor agonist BMS-470539 inhibits leucocyte trafficking in the inflamed vasculature.

BACKGROUND AND PURPOSE: Over three decades of research evaluating the biology of melanocortin (MC) hormones and synthetic peptides, activation of the MC type 1 (MC(1)) receptor has been identified as a viable target for the development of novel anti-inflammatory therapeutic agents. Here, we have tested a recently described selective agonist of MC(1) receptors, BMS-470539, on leucocyte/post-capillary venule interactions in murine microvascular beds. EXPERIMENTAL APPROACH: Intravital microscopy of two murine microcirculations were utilized, applying two distinct modes of promoting inflammation. The specificity of the effects of BMS-470539 was assessed using mice bearing mutant inactive MC(1) receptors (the recessive yellow e/e colony). KEY RESULTS: BMS-470539, given before an ischaemia-reperfusion protocol, inhibited cell adhesion and emigration with no effect on cell rolling, as assessed 90 min into the reperfusion phase. These properties were paralleled by inhibition of tissue expression of both CXCL1 and CCL2. Confocal investigations of inflamed post-capillary venules revealed immunostaining for MC(1) receptors on adherent and emigrated leucocytes. Congruently, the anti-inflammatory properties of BMS-470539 were lost in mesenteries of mice bearing the inactive mutant MC(1) receptors. Therapeutic administration of BMS-470539 stopped cell emigration, but did not affect cell adhesion in the cremasteric microcirculation inflamed by superfusion with platelet-activating factor. CONCLUSIONS AND IMPLICATIONS: Activation of MC(1) receptors inhibited leucocyte adhesion and emigration. Development of new chemical entities directed at MC(1) receptors could be a viable approach in the development of novel anti-inflammatory therapeutic agents with potential application to post-ischaemic conditions.

Fluctuation of annexin-A1 positive mast cells in chronic granulomatous inflammation.

OBJECTIVE: We have applied here a model of chronic granulomatous inflammation to study the profile of mast cell activation and their expression of annexin-A1 in the nodular lesion. MATERIALS: Granulomatous inflammation was induced by injection of croton oil and Freund's complete adjuvant (CO/FCA) into the dorsal air-pouches of mice. Skin tissue samples were collected from control group (24 h time-point; i. e. before disease development) and 7, 14, 21, 28 and 42 days post-CO/FCA treatment. RESULTS: Histopathological analyses revealed an on-going inflammation characterized by an increased number of activated mast cells at sites of the chronic inflammatory reaction in all experimental groups. Immunohistochemical analysis showed skin mast cells highly immunoreactive for annexin-A1, both at an initial (day 7) and a delayed (day 28) phase of the inflammatory reaction. CONCLUSIONS: The observed time-dependent modulation of mast cell activation, during the granulomatous injury, indicates that multiple pathways centred on annexin-A1 might become activated at different stages of this chronic inflammatory response, including the delayed and pro-resolving phase.

Annexin-A1: a pivotal regulator of the innate and adaptive immune systems.

The glucocorticoids are the most potent anti-inflammatory drugs that we possess and are effective in a wide variety of diseases. Although their action is known to involve receptor mediated changes in gene transcription, the exact mechanisms whereby these bring about their pleiotropic action in inflammation are yet to be totally understood. Whilst many different genes are regulated by the glucocorticoids, we have identified one particular protein-annexin A1 (Anx-A1)-whose synthesis and release is strongly regulated by the glucocorticoids in many cell types. The biology of this protein, as revealed by studies using transgenic animals, peptide mimetics and neutralizing antibodies, speaks to its role as a key modulator of both of the innate and adaptive immune systems. The mechanism whereby this protein exerts its effects is likely to be through the FPR receptor family-a hitherto rather enigmatic family of G protein coupled receptors, which are increasingly implicated in the regulation of many inflammatory processes. Here we review some of the key findings that have led up to the elucidation of this key pathway in inflammatory resolution.

Glucocorticoid treatment inhibits annexin-1 expression in rheumatoid arthritis CD4+ T cells.

OBJECTIVE: Annexin-1 (Anx-A1) has been recently shown to play a key role in T-cell activation and to be highly expressed in T cells from RA patients. Here, we investigated the effects of glucocorticoids (GCs) on Anx-A1 expression in T cells in vitro and in vivo. METHODS: To evaluate the effects of dexamethasone (Dex) on Anx-A1 expression, human peripheral blood T cells were incubated with Dex and then analysed by real-time PCR and western blotting. Similar experiments were carried out in vivo by measuring Anx-A1 levels in T cells from patients with RA before and after administration of steroids. RESULTS: Incubation of T cells with Dex decreased Anx-A1 levels in a time-dependent fashion and almost abolished its expression after 12 h. Stimulation of T cells pre-incubated with Dex for 12 h with anti-CD3/CD28 led to significant reduction of IL-2 production. Addition of human recombinant Anx-A1 to Dex-treated cells reversed the inhibitory effects of the steroids on anti-CD3/CD28-induced IL-2 production. Treatment of RA patients with steroid decreased Anx-A1 expression in T cells. CONCLUSIONS: GCs suppress Anx-A1 expression in T cells in vitro and in vivo. These results provide evidence for a novel pathway by which steroids regulate the adaptive immune response and suggest that Anx-A1 may represent a target for the treatment of autoimmune diseases.

Formyl peptide receptors and the regulation of ACTH secretion: targets for annexin A1, lipoxins, and bacterial peptides.

The N-formyl peptide receptors (FPRs) are a family of G-protein coupled receptors that respond to proinflammatory N-formylated bacterial peptides (e.g., formyl-Met-Leu-Phe, fMLF) and, thus, contribute to the host response to bacterial infection. Paradoxically, a growing body of evidence suggests that some members of this receptor family may also be targets for certain anti-inflammatory molecules, including annexin A1 (ANXA1), which is an important mediator of glucocorticoid (GC) action. To explore further the potential role of FPRs in mediating ANXA1 actions, we have focused on the pituitary gland, where ANXA1 has a well-defined role as a cell-cell mediator of the inhibitory effects of GCs on the secretion of corticotrophin (ACTH), and used molecular, genetic, and pharmacological approaches to address the question in well-established rodent models. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis identified mRNAs for four FPR family members in the mouse anterior pituitary gland, Fpr-rs1, Fpr-rs2, Fpr-rs6, and Fpr-rs7. Functional studies confirmed that, like dexamethasone, ANXA1 and two ANXA1-derived peptides (ANXA1(1-188) and ANXA1(Ac2-26)) inhibit the evoked release of ACTH from rodent anterior pituitary tissue in vitro. Fpr1 gene deletion failed to modify the pituitary responses to dexamethasone or ANXA1(Ac2-26). However, lipoxin A4 (LXA4, 0.02-2 microM, a lipid mediator with high affinity for Fpr-rs1) mimicked the inhibitory effects of ANXA1 on ACTH release as also did fMLF in high (1-100 microM) but not lower (10-100 nM) concentrations. Additionally, a nonselective FPR antagonist (Boc1, 100 microM) overcame the effects of dexamethasone, ANXA1(1-188), ANXA1(Ac2-26), fMLF, and LXA4 on ACTH release, although at a lower concentration (50 microM), it was without effect. Together, the results suggest that the actions of ANXA1 in the pituitary gland are independent of Fpr1 but may involve other FPR family members, in particular, Fpr-rs1 or a closely related receptor. They thus provide the first evidence for a role of the FPR family in the regulation of neuroendocrine function.

Inflammation-induced modulation of cellular galectin-1 and -3 expression in a model of rat peritonitis.

OBJECTIVE AND DESIGN: To investigate the effect of galectin-1 (Gal-1) and -3 (Gal-3) on leukocyte migration and analyze the expression of both galectins in inflammatory cells using a model of rat peritonitis. MATERIAL OR SUBJECTS: Sprague-Dawley rats (n = 4 per group). TREATMENT: Peritonitis was induced in animals through intraperitoneal injection of carrageenin (1.5 mg/kg) and rat mesenteries were analyzed at different time points (0, 4, 24 and 48h). For pharmacological treatment, rats received intravenous injection of Gal-1 or -3 (3microg/kg) followed by carrageenin. METHODS: Western blotting and immunoelectron microscopy analysis. Statistical analysis was performed using ANOVA followed by Bonferroni test. RESULTS: Pharmacological treatment with Gal-1, but not Gal-3, inhibited (approximately 50 %) leukocyte recruitment into the peritoneal cavity at 4 h time-point. In this early phase, immunogold staining of mesenteries showed a diminished Gal-3 expression in degranulated mast cells and Gal-1 in transmigrated neutrophils (approximately 20 % reduction compared to intravascular cells). In the later phases (24 and 48h), leukocyte turnover was associated with augmented Gal-1 expression in neutrophils and macrophages and Gal-3 in mast cells and macrophages. CONCLUSIONS: These results point to a balanced expression of cell-associated-Gal-1/Gal-3 and might impact on the development of new therapeutic strategies for inflammatory diseases.

The inhibition of neutrophil-endothelial cell adhesion by hyaluronan independent of CD44.

OBJECTIVE: To study the effect of hyaluronan on cell adhesion and recruitment both in vitro and in vivo, since hyaluronan both inhibits restenosis and is anti-inflammatory. When administered to animals undergoing angioplasty the recruitment of cells into the restenotic plaque is inhibited, as well as into inflammatory lesions. The recent discovery that ICAM-1 binds hyaluronan and exhibits the B(X(7))B HA binding motif, led us also to investigate whether cell adhesion could be modulated by hyaluronan. MATERIALS AND METHODS: Human neutrophils were adhered to human umbilical vein (HUVEC) or Ea.hy.926 HUVEC cells stimulated with phorbol myristate acetate (PMA) or tumour necrosis factor (TNFalpha). Neutrophil binding in vivo utilized FMLP-stimulated hamster cheek pouch post-capillary venules. RESULTS: Hyaluronan inhibited human neutrophil adhesion to both PMA and TNFalpha-stimulated HUVEC. Ea.hy.926 human immortal HUVECs expressed ICAM-1 in response to TNFalpha and PMA. E-selectin was also upregulated by 6 h with TNFalpha but not significantly with PMA. TNFalpha induced CD44 expression within 4 h, but PMA not significantly up to 6 h. However, specific binding of [125I]hyaluronan to Ea.hy.926 cells was increased by PMA-stimulation at 4 h. Neutrophil adhesion to PMA-stimulated Ea.hy.926 HUVECs was inhibited in a concentration dependent fashion by both anti-ICAM-1 and hyaluronan (1 ng/ml-10 microg/ml) at 4 h. At 1 mg/ml adhesion was stimulated by hyaluronan. Hyaluronan had no effect on neutrophil adhesion to resting Ea.hy.926 cells. Hyaluronan (25 mg/kg, i.v.) inhibited cell adhesion to FMLP-stimulated post capillary venules of the hamster cheek pouch, whilst leaving cell rolling unaffected. CONCLUSIONS: These results show that hyaluronan, at concentrations below those where intra-molecular associations occur, binds selectively to stimulated endothelial cells and inhibits neutrophil adhesion in vitro and in vivo via a mechanism which may involve molecules other than CD44, such as ICAM-1.

A twist in anti-inflammation: annexin 1 acts via the lipoxin A4 receptor.

The inflammatory response is a life-saving protective process mounted by the body to overcome pathogen infection and injury; however, in chronic inflammatory pathologies this response can become deregulated. The existence of specialized anti-inflammatory pathways/mediators that operate in the body to down-regulate inflammation have now emerged. Thus, persistence of inflammation leading to pathology could be due to malfunctioning of one or more of these counter-regulatory pathways. Here we focus on one of them, the anti-inflammatory mediator annexin 1, and provide an update on its inhibitory effects upon the leukocyte trafficking process. In particular, recent evidence that receptors of the formyl-peptide family, which includes also the lipoxin A4 receptor, could be the annexin 1 receptor(s) in the context of anti-inflammation might provide new avenues for exploiting this pathway for drug discovery.