Targeting the chemokine receptor CXCR4 with histamine analog to reduce inflammation in juvenile arthritis

Nassima Bekaddour; Nikaïa Smith; Benoit Beitz; Alba Llibre; Tom Dott; Anne Baudry; Anne-Sophie Korganow; Sébastien Nisole; Richard Mouy; Sylvain Breton; Brigitte Bader-Meunier; Darragh Duffy; Benjamin Terrier; Benoit Schneider; Pierre Quartier; Mathieu P Rodero; Jean-Philippe Herbeuval

doi:10.3389/fimmu.2023.1178172

Targeting the chemokine receptor CXCR4 with histamine analog to reduce inflammation in juvenile arthritis

Front Immunol. 2023 Sep 26:14:1178172. doi: 10.3389/fimmu.2023.1178172. eCollection 2023.

Authors

Nassima Bekaddour^{1

2}, Nikaïa Smith³, Benoit Beitz⁴, Alba Llibre³, Tom Dott⁴, Anne Baudry⁵, Anne-Sophie Korganow^{6

7

8}, Sébastien Nisole⁹, Richard Mouy¹⁰, Sylvain Breton^{10

11}, Brigitte Bader-Meunier^{10

12}, Darragh Duffy³, Benjamin Terrier¹³, Benoit Schneider⁵, Pierre Quartier^{10

12}, Mathieu P Rodero^{1

2}, Jean-Philippe Herbeuval^{1

2}

Affiliations

¹ Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR)-8601, Université Paris Cité, Paris, France.
² Chemistry and Biology, Modeling and Immunology for Therapy (CBMIT), Paris, France.
³ Translational Immunology Unit, Institut Pasteur, Université Paris Cité, Paris, France.
⁴ BIOASTER, Lyon, France.
⁵ Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR)-S1124, Team Stem Cells, Signaling and Prions, Université Paris Cité, Paris, France.
⁶ Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) - S1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
⁷ Department of Clinical Immunology and Internal Medicine, National Reference Center for Rare Autoimmune Diseases Centre National de Référence des maladies auto-immunes et systémiques rares de Strasbourg (RESO), Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
⁸ Unité de Formation et de Recherche (UFR) Medicine, University of Strasbourg, Strasbourg, France.
⁹ Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 9004, Montpellier, France.
¹⁰ Paediatric Haematology-Immunology and Rheumatology Department, Centre de référence des rhumatismes inflammatoires et maladies auto-immunes systémiques rares de l'enfant (RAISE) Reference Centre for Rare Diseases, Hôpital Universitaire Necker, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹¹ Paediatric Radiology Department, Necker-Enfants Malades University Hospital, Paris, France.
¹² Pediatric Immunology-Hematology and Rheumatology Unit, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM U1163, Necker-Enfants Malades Hospital, Assistance Publique - Hôpitaux de Paris (APHP), Imagine Institute, Université Paris Cité, Paris, France.
¹³ Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Assistance Publique Hôpitaux de Paris-Centre (APHP-CUP), Université de Paris, Paris, France.

Abstract

Introduction: Among immune cells, activated monocytes play a detrimental role in chronic and viral-induced inflammatory pathologies, particularly in Juvenile Idiopathic Arthritis (JIA), a childhood rheumatoid arthritis (RA) disease. The uncontrolled activation of monocytes and excessive production of inflammatory factors contribute to the damage of bone-cartilage joints. Despite the moderate beneficial effect of current therapies and clinical trials, there is still a need for alternative strategies targeting monocytes to treat RA.

Methods: To explore such an alternative strategy, we investigated the effects of targeting the CXCR4 receptor using the histamine analog clobenpropit (CB). Monocytes were isolated from the blood and synovial fluids of JIA patients to assess CB's impact on their production of key inflammatory cytokines. Additionally, we administered daily intraperitoneal CB treatment to arthritic mice to evaluate its effects on circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption, as indicators of disease progression.

Results: Our findings demonstrated that CXCR4 targeting with CB significantly inhibited the spontaneous and induced-production of key inflammatory cytokines by monocytes isolated from JIA patients. Furthermore, CB treatment in a mouse model of collagen-induce arthritis resulted in a significant decrease in circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption, leading to a reduction in disease progression.

Discussion: In conclusion, targeting CXCR4 with the small amino compound CB shows promise as a therapeutic option for chronic and viral-induced inflammatory diseases, including RA. CB effectively regulated inflammatory cytokine production of monocytes, presenting a potential targeted approach with potential advantages over current therapies. These results warrant further research and clinical trials to explore the full therapeutic potential of targeting CXCR4 with CB-like molecules in the management of various inflammatory diseases.

Keywords: arthritis; cytokines; inflammation; monocytes; treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arthritis, Juvenile* / drug therapy
Arthritis, Rheumatoid*
Bone Resorption*
Cytokines
Disease Progression
Histamine* / analogs & derivatives
Humans
Inflammation / drug therapy
Mice
Receptors, CXCR4

Substances

CXCR4 protein, human
Cytokines
Histamine
Receptors, CXCR4

Grants and funding

This research was financially supported by the Agence National de la Recherche sur le SIDA et les Hépatites (ANRS) under the grant awarded to J-PH for conducting the experiments. NB received a fellowship (AAP 2017-166) for this work. NS is a recipient of the European Molecular Biology Organization (EMBO) Long-Term Fellowship (LT-834-2017) and the Pasteur-Roux-Cantarini Fellowship.