Prodrugs of a CXC Chemokine-12 (CXCL12) Neutraligand Prevent Inflammatory Reactions in an Asthma Model in Vivo

Gasparik, Vincent; Daubeuf, François; Hachet‐Haas, Muriel; Rohmer, François; Gizzi, Patrick; Haiech, Jacques; Galzi, Jean‐Luc; Hibert, Marcel; Bron, Dominique; Frossard, Nelly

doi:10.1021/ml200017d

Cited by 24 publications

(40 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The compound is a prodrug; after in vivo cleavage of the phosphate group, it converts into the active chalcone 4 molecule that selectively binds CXCL12 and neutralizes its function. 24 Chalcone 4 was shown to prevent induction of CXCR4 signaling and CXCL12-mediated CXCR4 internalization in vitro. 23 To investigate whether elevated levels of circulating CXCL12 were required for mobilization of leukocytes and HPCs by AMD3100, we administered C4P IV (1.5 mmol/kg) to neutralize CXCL12 in the peripheral circulation.…”

Section: Resultsmentioning

confidence: 98%

“…21 As with AMD3100, preliminary studies investigating the anti-HIV activity of KRH3955 showed that a single dose of this drug elevated leukocyte counts in peripheral blood. 22 Here, we have made use of a specific CXCL12 neutraligand, chalcone 4-phosphate, 23,24 to address the question of whether an elevation of CXCL12 in the plasma is required for mobilization of HPCs and MPCs by these distinct CXCR4 antagonists.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Two distinct CXCR4 antagonists mobilize progenitor cells in mice by different mechanisms

et al. 2017

Self Cite

View full text Add to dashboard Cite

Pharmacological mobilization of hematopoietic progenitor cells (HPCs) is used clinically to harvest HPCs for bone marrow transplants. It is now widely accepted that the CXCR4:CXCL12 chemokine axis plays a critical role in the retention of HPCs in the bone marrow, and CXCR4 antagonists have been developed for their mobilization. The first of this class of drugs to be US Food and Drug Administration-approved was the bicyclam AMD3100. In addition to mobilizing HPCs and leukocytes in naïve mice, AMD3100 has been shown to mobilize mesenchymal progenitor cells (MPCs) in vascular endothelial growth factor (VEGF-A) pretreated mice. AMD3100 binds to the transmembrane region of CXCR4 and is thought to mobilize HPCs by reversing the gradient of CXCL12 across the bone marrow endothelium. Consistent with this hypothesis, our data show that selective neutralization of CXCL12, with chalcone 4-phosphate (C4P), inhibited AMD3100-stimulated mobilization of HPCs and leukocytes in naïve mice and MPCs in VEGF-A pretreated mice. In contrast it is shown here that the CXCR4 antagonist KRH3955 that binds to the extracellular loop of CXCR4 does not reverse the CXCL12 chemokine gradient. However, this drug efficiently mobilizes HPCs, a response that is not inhibited by C4P. In contrast, KRH3955 does not mobilize MPCs in VEGF-A pretreated mice. These data suggest that CXCR4 antagonists that bind to distinct regions of the receptor mobilize progenitor cells by distinct molecular mechanisms

show abstract

Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Two distinct CXCR4 antagonists mobilize progenitor cells in mice by different mechanisms

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…AMD3100 (or plerixafor) was from Sigma-Aldrich. Chalcone 4 was prepared as described in Gasparik et al 16 and in supplemental Methods. Descriptions of the culture and transfection are provided in supplemental Methods.…”

Section: Reagents Cell Culture and Transfectionmentioning

confidence: 99%

Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice

Balabanian

Brotin

Biajoux

et al. 2012

Blood

Self Cite

107

154

View full text Add to dashboard Cite

Desensitization controls G protein-dependent signaling of chemokine receptors. We investigate the physiologic implication of this process for CXCR4 in a mouse model harboring a heterozygous mutation of the Cxcr4 gene, which engenders a desensitization-resistant receptor. Such anomaly is linked to the warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome, a human rare combined immunodeficiency. Cxcr4(+/mutant(1013)) mice display leukocytes with enhanced responses to Cxcl12 and exhibit leukopenia as reported in patients. Treatment with CXCL12/CXCR4 antagonists transiently reverses blood anomalies, further demonstrating the causal role of the mutant receptor in the leukopenia. Strikingly, neutropenia occurs in a context of normal bone marrow architecture and granulocyte lineage maturation, indicating a minor role for Cxcr4-dependent signaling in those processes. In contrast, Cxcr4(+/1013) mice show defective thymopoiesis and B-cell development, accounting for circulating lymphopenia. Concomitantly, mature T and B cells are abnormally compartmentalized in the periphery, with a reduction of primary follicles in the spleen and their absence in lymph nodes mirrored by an unfurling of the T-cell zone. These mice provide a model to decipher the role of CXCR4 desensitization in the homeostasis of B and T cells and to investigate which manifestations of patients with WHIM syndrome may be overcome by dampening the gain of CXCR4 function.

show abstract

“…Chalcone 4 was identified as an inhibitor of the interaction between CXCR4 or CXCR7 and their ligand CXCL12 [6, 14] through binding to the chemokine in a neutralizing-like manner rather than on its receptors [15]. Chalcone 4 was therefore called a neutraligand.…”

Section: Introductionmentioning

confidence: 99%

“…Chalcone 4 was therefore called a neutraligand. Administered intranasally, chalcone 4 decreased the recruitment of inflammatory cells, in particular eosinophils, in a mouse model of allergic eosinophilic airway inflammation [6, 14]. Furthermore, chalcone 4 derivatives, modified as highly soluble prodrugs, attenuated at very low doses the inflammatory reaction in an allergic airway hypereosinophilia model [14].…”

Section: Introductionmentioning

confidence: 99%

Decreased Migration of Dendritic Cells into the Jugular-Nodose Ganglia by the CXCL12 Neutraligand Chalcone 4 in Ovalbumin-Sensitized Asthmatic Mice

Heck¹,

Daubeuf²,

Le³

et al. 2017

Neuroimmunomodulation

Self Cite

View full text Add to dashboard Cite

Objective: The chemokine CXCL12 interacting with the CXC receptor 4 (CXCR4) has been reported to play a role in the development and progression of bronchial asthma, but its mechanism of action is still unknown. The objective of this study was to assess the effect of the CXCL12 neutraligand chalcone 4 on the migration of dendritic cells (DCs) in a murine model of allergic airway inflammation. Methods: A 21-day ovalbumin (OVA)-induced allergic-airway T_H2 inflammation model in BALB/c mice was used. Four groups were sensitized with OVA adsorbed on alum and challenged either with OVA or saline for 4 days. Mice were treated intranasally with chalcone 4 (300 nmol/kg body weight) or solvent 2 h before each OVA or saline challenge; 24 h after the last challenge, CD11c⁺F4/80^– DCs were counted in the bronchoalveolar lavage. Jugular-nodose ganglion complex (JNC) sections were sampled, and for immunofluorescence staining, cryocut sections were prepared. MHC II⁺F4/80^– DCs as well as calcitonin gene-related peptide (CGRP)- and substance P (SP)-positive neuronal cell bodies were analyzed. Results: In OVA-challenged mice, chalcone 4 caused a significantly decreased DC/neuron ratio in the JNC from 51.7% in solvent-treated to 32.6% in chalcone 4-treated mice. In parallel, chalcone 4 also decreased the DC population in BALF from 11.5 × 10³ cells in solvent to 4.5 × 10³ cells in chalcone 4-treated mice. By contrast, chalcone 4 had no effect on the expression of the neuropeptides CGRP and SP in JNC. Conclusion: This study reported the CXCL12 neutraligand chalcone 4 to affect DC infiltration into the airways and airway ganglia as well as to decrease airway eosinophilic inflammation and, therefore, validated CXCL12 as a new target in allergic disease models of asthma.

show abstract

Prodrugs of a CXC Chemokine-12 (CXCL12) Neutraligand Prevent Inflammatory Reactions in an Asthma Model in Vivo

Cited by 24 publications

References 19 publications

Two distinct CXCR4 antagonists mobilize progenitor cells in mice by different mechanisms

Two distinct CXCR4 antagonists mobilize progenitor cells in mice by different mechanisms

Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice

Decreased Migration of Dendritic Cells into the Jugular-Nodose Ganglia by the CXCL12 Neutraligand Chalcone 4 in Ovalbumin-Sensitized Asthmatic Mice

Contact Info

Product

Resources

About