Deficiency of Annexin A1 in CD4+ T Cells Exacerbates T Cell–Dependent Inflammation

Yang, Yuan; Song, Wuqi; Deane, James A.; Kao, Wenping; Ooi, Joshua D.; Ngo, Devi; Kitching, A. Richard; Morand, Eric Francis; Hickey, Michael J.

doi:10.4049/jimmunol.1202236

Cited by 65 publications

(66 citation statements)

References 56 publications

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“…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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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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“…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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“…The exact role of ANXA1 in the immune response is unclear. Some studies have shown ANXA1 to be important in inhibiting T cell activation (14,15), whereas others have shown that ANXA1 can augment T cell activation and skew T cell polarization to a Th1 phenotype (16,17) and that ANXA1 is important in negative and positive selection (18).…”

Section: T He Tlrs Are Important Pattern Recognition Receptors (Prrs)mentioning

confidence: 99%

Annexin-A1 Regulates TLR-Mediated IFN-β Production through an Interaction with TANK-Binding Kinase 1

Bist

Shu

Lee

et al. 2013

The Journal of Immunology

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TLRs play a pivotal role in the recognition of bacteria and viruses. Members of the family recognize specific pathogen sequences to trigger both MyD88 and TRIF-dependent pathways to stimulate a plethora of cells. Aberrant activation of these pathways is known to play a critical role in the development of autoimmunity and cancer. However, how these pathways are entirely regulated is not fully understood. In these studies, we have identified Annexin-A1 (ANXA1) as a novel regulator of TLR-induced IFN-β and CXCL10 production. We demonstrate that in the absence of ANXA1, mice produce significantly less IFN-β and CXCL10, and macrophages and plasmacytoid dendritic cells have a deficiency in activation following polyinosinic:polycytidylic acid administration in vivo. Furthermore, a deficiency in activation is observed in macrophages after LPS and polyinosinic:polycytidylic acid in vitro. In keeping with these findings, overexpression of ANXA1 resulted in enhanced IFN-β and IFN-stimulated responsive element promoter activity, whereas silencing of ANXA1 impaired TLR3- and TLR4-induced IFN-β and IFN-stimulated responsive element activation. In addition, we show that the C terminus of ANXA1 directly associates with TANK-binding kinase 1 to regulate IFN regulatory factor 3 translocation and phosphorylation. Our findings demonstrate that ANXA1 plays an important role in TLR activation, leading to an augmentation in the type 1 IFN antiviral cytokine response.

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“…CS was induced as described previously (29,32,34,35). In brief, mice were sensitized by the application of 50 ml 5% oxazolone (4-ethoxymethylene-2-phenyl-2-oxazolin-5-one) (Sigma-Aldrich, St. Louis, MO) in an acetone/ olive oil vehicle (4:1) to a shaved region on the back.…”

Section: Contact Sensitivitymentioning

confidence: 99%

Regulatory T Cells Dynamically Regulate Selectin Ligand Function during Multiple Challenge Contact Hypersensitivity

Abeynaike

Deane

Westhorpe

et al. 2014

The Journal of Immunology

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Regulatory T cells (Tregs) play critical roles in restricting T cell–mediated inflammation. In the skin, this is dependent on expression of selectin ligands required for leukocyte rolling in dermal microvessels. However, whether there are differences in the molecules used by Tregs and proinflammatory T cells to undergo rolling in the skin remains unclear. In this study, we used spinning disk confocal microscopy in Foxp3-GFP mice to visualize rolling of endogenous Tregs in dermal postcapillary venules. Tregs underwent consistent but low-frequency rolling interactions under resting and inflamed conditions. At the early stage of the response, Treg adhesion was minimal. However, at the peak of inflammation, Tregs made up 40% of the adherent CD4+ T cell population. In a multiple challenge model of contact hypersensitivity, rolling of Tregs and conventional CD4+ T cells was mostly dependent on overlapping contributions of P- and E-selectin. However, after a second challenge, rolling of Tregs but not conventional CD4+ T cells became P-selectin independent, and Tregs showed reduced capacity to bind P-selectin. Moreover, inhibition of E-selectin at this time point resulted in exacerbation of inflammation. These findings demonstrate that in this multiple challenge model of inflammation, Treg selectin binding capacity and the molecular basis of Treg rolling can be regulated dynamically.

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Deficiency of Annexin A1 in CD4+ T Cells Exacerbates T Cell–Dependent Inflammation

Cited by 65 publications

References 56 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

Annexin-A1 Regulates TLR-Mediated IFN-β Production through an Interaction with TANK-Binding Kinase 1

Regulatory T Cells Dynamically Regulate Selectin Ligand Function during Multiple Challenge Contact Hypersensitivity

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