Formyl peptide receptor activation inhibits the expansion of effector T cells and synovial fibroblasts and attenuates joint injury in models of rheumatoid arthritis

Odobasic, Dragana; Jia, Yuan; Kao, Wenping; Fan, Huapeng; Wei, Xuemin; Gu, Rong; Ngo, Devi; Kitching, A. Richard; Holdsworth, Stephen R.; Morand, Eric Francis; Yang, Yuan

doi:10.1016/j.intimp.2018.05.028

Cited by 32 publications

(31 citation statements)

References 69 publications

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“…A large number of publications have highlighted the immunomodulatory role of FPR2 by having both pro-and anti-inflammatory activities [1,2,60]. Thus, agonists as well as antagonists that target FPR2 may have therapeutic potential [61][62][63][64]. Accordingly, numerous FPR2 ligands have been identified and characterized through different approaches, but not until very recently, the agonist termed Act-389949 stated to be FPR2 specific, was introduced into a phase I clinical trial [36].…”

Section: Discussionmentioning

confidence: 99%

Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949

Lind

Sundqvist

Holmdahl

et al. 2019

Preprint

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Despite the steadily increased numbers of formyl peptide receptor (FPR) ligands identified over the years, few have been characterized in studies using animal disease models and even less have entered clinical trials in human subjects. A small-molecule compound, Act-389949, was however recently tested in a phase I clinical trial and found to be safe and well tolerated in healthy human subjects. The desired anti-inflammatory property of Act-389949 was proposed to be mediated through FPR2, one of the FPRs expressed in neutrophils, but no basic characterization was included in the study. To gain more insights into FPR2 recognition of this first-in-class compound for future utility of the agonist, we have in this study determined the receptor preference and down-stream signaling characteristics induced by Act-389949 in human blood neutrophils isolated from healthy donors. Our data demonstrate that Act-389949 is an agonist for FPR2 that triggers functional/signaling repertoires comparable to what has been earlier described for other FPR2 agonists, including neutrophil chemotaxis, granule mobilization and activation of the NADPH-oxidase. In fact, Act-389949 was found to be as potent as the prototype FPR2 peptide agonist WKYMVM and had the advantage of being resistant to oxidation by the MPO-H2O2-halide derived oxidants, as compared to the sensitive WKYMVM. The down-stream signals generated by Act-389949 include an FPR2-dependent and Gαq-independent transient rise in intracellular Ca 2+ and recruitment of β-arrestin. In summary, our data show that Act-389949 serves as an excellent tool-compound for further dissection of FPR2-regulated activities in vitro and in vivo. Potent and stable FPR ligands such as Act-389949 may therefore be used to develop the next generation of FPR signaling regulating anti-inflammatory therapeutics.

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Section: Discussionmentioning

confidence: 99%

Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949

Lind

Sundqvist

Holmdahl

et al. 2019

Preprint

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“…ANX A1 participates in several signalling pathways, among them up‐regulation of sphingosine‐1‐phosphate phosphatase (SGPP2), an enzyme involved in the degradation of sphingosine‐1‐phosphate (S1P), and the up‐regulation of jagged 1 protein (JAG1) genes after ANX A1–ALXR engagement on human cells . Both pathways are involved in T cell maturation, differentiation and migration from lymphoid organs, but not in B cell development, suggesting an indirect ANX A1 impact to B lymphocytes via T cell activation, although a direct B cell effect is also possible .…”

Section: Discussionmentioning

confidence: 99%

Suppression of autoreactive T and B lymphocytes by anti-annexin A1 antibody in a humanized NSG murine model of systemic lupus erythematosus

Mihaylova

Chipinski

Bradyanova

et al. 2019

Clinical and Experimental Immunology

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Summary Systemic lupus erythematosus is a chronic inflammatory disease which involves multiple organs. Self‐specific B and T cells play a main role in the pathogenesis of lupus and have been defined as a logical target for selective therapy. The protein annexin A1 (ANX A1) is a modulator of the immune system involving many cell types. An abnormal expression of ANX A1 was found on activated B and T cells during autoimmunity, suggesting its importance as a potential therapeutic target. We hypothesize that it may be possible to down‐regulate the activity of autoreactive T and B cells from lupus patients in a humanized immunodeficient mouse model by treating them with an antibody against ANX A1. When cultured in the presence of anti‐ANX A1, peripheral blood mononuclear cells (PBMC) from lupus patients showed a decreased number of immunoglobulin (Ig)G anti‐dsDNA antibody‐secreting plasma cells, decreased T cell proliferation and expression of activation markers and increased B and T cell apoptosis. We employed a humanized model of SLE by transferring PBMCs from lupus patients to immunodeficient non‐obese diabetic‐severe combined immunodeficient (NOD‐SCID) mice. The humanized animals presented autoantibodies, proteinuria and immunoglobulin deposition in the renal glomeruli. Treatment of these NOD‐SCID mice with an anti‐ANX A1 antibody prevented appearance of anti‐DNA antibodies and proteinuria, while the phosphate‐buffered saline (PBS)‐injected animals had high levels after the transfer. The treatment reduced the levels of autoantibodies to several autoantigens, lupus‐associated cytokines and disease symptoms.

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“…Some studies demonstrate AnxA1 to be an FPR1 agonist, while others show it as an FPR2 agonist; hence, it likely activates both. One study demonstrated its role in the attenuation of rheumatoid arthritis symptoms by decreasing fibroblast-like synoviocyte proliferation via FPR2 [79]. However, another study showed that AnxA1 initiated autocrine signaling in breast cancer via FPR1 and led to an increase in tumor growth and metastasis [80].…”

Section: Host-derived Fpr Ligandsmentioning

confidence: 99%

Chemotactic Ligands that Activate G-Protein-Coupled Formylpeptide Receptors

Krepel

Wang

2019

IJMS

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Leukocyte infiltration is a hallmark of inflammatory responses. This process depends on the bacterial and host tissue-derived chemotactic factors interacting with G-protein-coupled seven-transmembrane receptors (GPCRs) expressed on the cell surface. Formylpeptide receptors (FPRs in human and Fprs in mice) belong to the family of chemoattractant GPCRs that are critical mediators of myeloid cell trafficking in microbial infection, inflammation, immune responses and cancer progression. Both murine Fprs and human FPRs participate in many patho-physiological processes due to their expression on a variety of cell types in addition to myeloid cells. FPR contribution to numerous pathologies is in part due to its capacity to interact with a plethora of structurally diverse chemotactic ligands. One of the murine Fpr members, Fpr2, and its endogenous agonist peptide, Cathelicidin-related antimicrobial peptide (CRAMP), control normal mouse colon epithelial growth, repair and protection against inflammation-associated tumorigenesis. Recent developments in FPR (Fpr) and ligand studies have greatly expanded the scope of these receptors and ligands in host homeostasis and disease conditions, therefore helping to establish these molecules as potential targets for therapeutic intervention.

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Formyl peptide receptor activation inhibits the expansion of effector T cells and synovial fibroblasts and attenuates joint injury in models of rheumatoid arthritis

Cited by 32 publications

References 69 publications

Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949

Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949

Suppression of autoreactive T and B lymphocytes by anti-annexin A1 antibody in a humanized NSG murine model of systemic lupus erythematosus

Chemotactic Ligands that Activate G-Protein-Coupled Formylpeptide Receptors

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