Anti-inflammatory effects of annexin-1: stimulation of IL-10 release and inhibition of nitric oxide synthesis

Ferlazzo, Viviana; D’Agostino, Pietro; Milano, Salvatore; Caruso, Rosalba; Feo, Salvatore; Cillari, Enrìco; Parente, Luca

doi:10.1016/s1567-5769(03)00133-4

Cited by 87 publications

(68 citation statements)

References 26 publications

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“…In vivo injections of anti-inflammatory doses of AnxA1 (26) led to IL-10 production in an ALXdependent manner, as demonstrated using a mouse colony deficient in the ortholog for the human receptor (4). Some evidence for a link between AnxA1 and IL-10 has been advanced in the literature using macrophages (27) and in models of gut injury (28). Our data provide molecular support to this pathway, linking the protein AnxA1-a master regulator of resolution (29)-and the cytokine IL-10 to ALX homodimerization.…”

Section: Discussionsupporting

confidence: 65%

Ligand-specific conformational change of the G-protein–coupled receptor ALX/FPR2 determines proresolving functional responses

Cooray

Gobbetti

Montero‐Melendez

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

257

252

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Formyl-peptide receptor type 2 (FPR2), also called ALX (the lipoxin A4 receptor), conveys the proresolving properties of lipoxin A 4 and annexin A1 (AnxA1) and the proinflammatory signals elicited by serum amyloid protein A and cathelicidins, among others. We tested here the hypothesis that ALX might exist as homo-or heterodimer with FPR1 or FPR3 (the two other family members) and operate in a ligand-biased fashion. Coimmunoprecipitation and bioluminescence resonance energy transfer assays with transfected HEK293 cells revealed constitutive dimerization of the receptors; significantly, AnxA1, but not serum amyloid protein A, could activate ALX homodimers. A p38/MAPK-activated protein kinase/heat shock protein 27 signaling signature was unveiled after AnxA1 application, leading to generation of IL-10, as measured in vitro (in primary monocytes) and in vivo (after i.p. injection in the mouse). The latter response was absent in mice lacking the ALX ortholog. Using a similar approach, ALX/FPR1 heterodimerization evoked using the panagonist peptide Ac2-26, identified a JNK-mediated proapoptotic path that was confirmed in primary neutrophils. These findings provide a molecular mechanism that accounts for the dual nature of ALX and indicate that agonist binding and dimerization state contribute to the conformational landscape of FPRs.inflammation | leukocyte | resolution signaling G -protein-coupled receptors (GPCRs) constitute a large family of cell surface receptors that share structural characteristics and perform pivotal biological functions, transducing signals from hormones, autacoids, and chemokines. The human GPCR termed "ALX/FPR2" (formyl peptide receptor type 2 or lipoxin A 4 receptor, hereafter referred to as "ALX") is a unique GPCR, shown to convey signals induced by proteins, peptides, and lipid ligands (1). ALX belongs to a small family of receptors that is also activated by formylated peptides, short amino acid sequences with an N-terminal formyl group released by pathogenic and commensal bacteria, as well as by mitochondria upon cell damage. There are three human FPRs and they are termed FPR1, ALX, and FPR3 (2). In view of their different nature and potential engagement with a large number endogenous and exogenous ligands, elucidation of FPR functions may reveal important biological pathways.ALX is an unconventional receptor for the diversity of its agonists and because it can convey contrasting biological signals. The proresolving and anti-inflammatory properties of the protein annexin A1 (AnxA1) and the lipid lipoxin A 4 (LXA 4 ), which include neutrophil apoptosis and macrophage efferocytosis, are mediated by this receptor, as shown using pharmacological approaches (1, 3) and more recently with knockout mouse models (4). At the same time, the proinflammatory responses elicited by the cathelicidin-associated antimicrobial peptide LL-37 and serum amyloid protein A (SAA) are also mediated by ALX, which modulates leukocyte activation, recruitment to the site of inflammation, and lifespan (5-7). Moreover,...

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Section: Discussionsupporting

confidence: 65%

Ligand-specific conformational change of the G-protein–coupled receptor ALX/FPR2 determines proresolving functional responses

Cooray

Gobbetti

Montero‐Melendez

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

257

252

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“…34,35 Annexin I, a newly defined endogenous ligand for tethering and internalization of apoptotic cells, can stimulate IL-10 production and inhibit nitric oxide synthesis. 15 The present study demonstrates that inducing production of IL-10 by crambene is temporally coincident with clearance of apoptotic cells and that the release of the IL-10 is downstream of phagocytosis (Figures 8A, 12, and 13). Moreover, our in vitro data also support that phagocytosis of apoptotic acinar cells indeed stimulates the production of IL-10 ( Figure 9).…”

Section: Discussionsupporting

confidence: 50%

“…12 For instance, the release of transforming growth factor (TGF)-␤1 by macrophages may be mediated by PSR during the clearance of apoptotic cells, 13,14 whereas interleukin (IL)-10 is secreted by macrophages engaging with apoptotic cells via annexin I-dependent mechanisms. 15 It is therefore reasonable to postulate that following apoptosis of pancreatic acinar cells, phagocytosis triggers an anti-inflammatory response, which in turn protects against AP.…”

mentioning

confidence: 99%

Induction of Apoptosis by Crambene Protects Mice against Acute Pancreatitis via Anti-Inflammatory Pathways

Cao

Adhikari

Clément

et al. 2007

The American Journal of Pathology

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Apoptosis is a teleologically beneficial form of cell death in acute pancreatitis. Our previous work has demonstrated that induction of pancreatic acinar cell apoptosis by crambene protects mice against acute pancreatitis. However, little is known about how the induction of apoptosis reduces the severity of acute pancreatitis. Because the clearance of apoptotic cells might suppress inflammation and critically regulate immune responses, we postulate that clearance of apoptotic cells stimulates an anti-inflammatory response, which has a protective action against acute pancreatitis. To test this hypothesis, induction of apoptosis in acute pancreatitis in vivo and co-cultures of peritoneal resident macrophages with apoptotic acinar cells in vitro were used as experimental systems, testing expression of phagocytic receptors and levels of inflammatory mediators. Moreover, neutralizing anti-interleukin (IL)-10 monoclonal antibody (2.5 mg/ kg) was used before the induction of apoptosis in acute pancreatitis, testing whether the protection from apoptosis induction would be removed. Our study showed that clearance of apoptotic acinar cells, which may occur essentially through the CD36-positive macrophage, stimulates the release of anti-inflammatory mediators like IL-10. IL-10 plays an important role in crambene-induced protection in acute pancreatitis. Thus, induction of pancreatic acinar cell apoptosis by crambene protects mice against acute pancreatitis via induction of anti-inflammatory pathways. (Am J Pathol

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“…Dexamethasone-induced synthesis of annexin-like proteins by J774 murine macrophages inhibited LPS-induced nitric oxide production and expression of inducible nitric oxide synthase (D'Acquisto et al 1997). Similar studies with J774 cells showed identical results using a truncated peptide fragment of ANXA1, residues 1-188 when pre-incubated for 1 h prior to LPS challenge (Wu et al 1995) and with recombinant ANXA1 and peptide Ac2-26 in J774 cells (Ferlazzo et al 2003) and LPSprimed primary rat alveolar macrophages (Kamal et al 1998). Interestingly, inhibition of nitric oxide release and inducible nitric oxide synthase expression by recombinant ANXA1 were associated with dose and time-dependent increases in IL-10 protein and a concomitant reduction in IL-12 mRNA (Ferlazzo et al 2003) providing new insights in to the potential mechanism of inhibition of nitric oxide synthesis in macrophages.…”

Section: Anxa1 Actions On Monocytes and Macrophagesmentioning

confidence: 71%

An overview of the effects of annexin 1 on cells involved in the inflammatory process

Kamal

Flower

Perretti

2005

Mem. Inst. Oswaldo Cruz

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Anti-inflammatory effects of annexin-1: stimulation of IL-10 release and inhibition of nitric oxide synthesis

Cited by 87 publications

References 26 publications

Ligand-specific conformational change of the G-protein–coupled receptor ALX/FPR2 determines proresolving functional responses

Ligand-specific conformational change of the G-protein–coupled receptor ALX/FPR2 determines proresolving functional responses

Induction of Apoptosis by Crambene Protects Mice against Acute Pancreatitis via Anti-Inflammatory Pathways

An overview of the effects of annexin 1 on cells involved in the inflammatory process

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