The impact of endogenous annexin A1 on glucocorticoid control of inflammatory arthritis

Patel, Hetal; Kornerup, Kristin N.; Sampaio, André Luiz Franco; D’Acquisto, Fulvio; Seed, Michael; Girol, Ana Paula; Gray, Mohini; Pitzalis, Costantino; Oliani, Sônia Maria; Perretti, Mauro

doi:10.1136/annrheumdis-2011-201180

Cited by 72 publications

(53 citation statements)

References 62 publications

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“…These findings are at odds with those of a recent study in which increased arthritis severity in AnxA1 −/− mice was not observed in this model (Patel et al, 2012), although these authors did observe reduced efficacy of the glucocorticoid dexamethasone in the absence of AnxA1. In that study, arthritis was induced with a higher dose of K/BxN serum than that used in the current study.…”

Section: Figurecontrasting

confidence: 57%

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A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis

Kao

Jia

et al. 2014

British J Pharmacology

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Background and PurposeAnnexin 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 ApproachArthritis 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 ResultsTreatment 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 ImplicationsThe 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.

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Section: Figurecontrasting

confidence: 57%

“…AnxA1 has been shown to ameliorate disease in several animal models of inflammation, including arthritis (Yang et al, 1999;2013b;Patel et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis

Kao

Jia

et al. 2014

British J Pharmacology

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“…Although the anti-inflammatory activities of AnxA1 and its mimetic peptides, including Ac2-26, have been explored in several in vivo and in vitro investigations (16,(18)(19)(20)26), the role of exogenous AnxA1 in ocular inflammatory processes has not been elucidated, and there are no studies on the administration of Ac2-26 in ocular tissues. Given the common side effects of the current therapies used to treat uveitis (4,5,15), we evaluated the effects of endogenous and exogenous AnxA1 protein in rodent ocular tissues in EIU and an in vitro LPS-inflamed RPE human cell system and further evaluated AnxA1's mechanism of action.…”

mentioning

confidence: 99%

Anti-Inflammatory Mechanisms of the Annexin A1 Protein and Its Mimetic Peptide Ac2-26 in Models of Ocular Inflammation In Vivo and In Vitro

Girol

Mimura

Drewes

et al. 2013

The Journal of Immunology

106

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Annexin A1 (AnxA1) is a protein that displays potent anti-inflammatory properties, but its expression in eye tissue and its role in ocular inflammatory diseases have not been well studied. We investigated the mechanism of action and potential uses of AnxA1 and its mimetic peptide (Ac2-26) in the endotoxin-induced uveitis (EIU) rodent model and in human ARPE-19 cells activated by LPS. In rats, analysis of untreated EIU after 24 and 48 h or EIU treated with topical applications or with a single s.c. injection of Ac2-26 revealed the anti-inflammatory actions of Ac2-26 on leukocyte infiltration and on the release of inflammatory mediators; the systemic administration of Boc2, a formylated peptide receptor (fpr) antagonist, abrogated the peptide’s protective effects. Moreover, AnxA1−/− mice exhibited exacerbated EIU compared with wild-type animals. Immunohistochemical studies of ocular tissue showed a specific AnxA1 posttranslational modification in EIU and indicated that the fpr2 receptor mediated the anti-inflammatory actions of AnxA1. In vitro studies confirmed the roles of AnxA1 and fpr2 and the protective effects of Ac2-26 on the release of chemical mediators in ARPE-19 cells. Molecular analysis of NF-κB translocation and IL-6, IL-8, and cyclooxygenase-2 gene expression indicated that the protective effects of AnxA1 occur independently of the NF-κB signaling pathway and possibly in a posttranscriptional manner. Together, our data highlight the role of AnxA1 in ocular inflammation, especially uveitis, and suggest the use of AnxA1 or its mimetic peptide Ac2-26 as a therapeutic approach.

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“…In monocytes and macrophages they inhibit production of proinflammatory cytokines as the result of an interaction between GC receptor monomers and proinflammatory transcription factors, such as NF-kB or AP-1, in a process called "transrepression" (4,5). GCs also induce anti-inflammatory mediators in monocytes/macrophages (e.g., annexin A1) (6,7).…”

mentioning

confidence: 99%

Immune Suppression via Glucocorticoid-Stimulated Monocytes: A Novel Mechanism To Cope with Inflammation

Varga

Ehrchen

Brockhausen

et al. 2014

The Journal of Immunology

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Glucocorticoids (GCs) are used as first-line therapies for generalized suppression of inflammation (e.g., allergies or autoimmune diseases), but their long-term use is limited by severe side effects. Our previous work revealed that GCs induced a stable anti-inflammatory phenotype in monocytes, the GC-stimulated monocytes (GCsMs) that we exploited for targeted GC-mediated therapeutic effects. We demonstrate that GCsMs interact with T cells in suppressing proliferation, as well as cytokine release of CD8+ and, especially, CD4+ T cells in vitro, and that they support generation of Foxp3+ cells. Therefore, we tested their immunosuppressive potential in CD4+ T cell–induced colitis in vivo. We found that injection of GCsMs into mice with severe colitis abolished the inflammation and resulted in significant clinical improvement within a few days. T cells recovered from GCsM-treated mice exhibited reduced secretion of proinflammatory cytokines IFN-γ and IL-17. Furthermore, clusters of Foxp3+ CD4+ T cells were detectable at local sites of inflammation in the colon. Thus, GCsMs are able to modify T cell responses in vitro and in vivo, as well as to downregulate and clinically cure severe T cell–mediated colitis.

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The impact of endogenous annexin A1 on glucocorticoid control of inflammatory arthritis

Cited by 72 publications

References 62 publications

A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis

A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis

Anti-Inflammatory Mechanisms of the Annexin A1 Protein and Its Mimetic Peptide Ac2-26 in Models of Ocular Inflammation In Vivo and In Vitro

Immune Suppression via Glucocorticoid-Stimulated Monocytes: A Novel Mechanism To Cope with Inflammation

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