An Antedrug of the CXCL12 Neutraligand Blocks Experimental Allergic Asthma without Systemic Effect in Mice

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

doi:10.1074/jbc.m112.449348

Cited by 32 publications

(39 citation statements)

References 67 publications

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“…The use of neutraligands is a very interesting therapeutic strategy because they do not bind the chemokine receptors and thereby do not modify cell homeostasis [21, 23]. We recently described the anti-inflammatory activity of chalcone 4 in a murine model of allergic airway hypereosinophilia [6, 14, 15]. The present study confirmed the anti-inflammatory effect of chalcone 4 treatment in asthma, with decreased numbers of inflammatory cells in BALF.…”

Section: Discussionsupporting

confidence: 72%

“…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%

“…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%

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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

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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.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

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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

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“…Previous reports have demonstrated that inhibition of CXCL12/CXCR4 signaling attenuated allergic lung inflammation and AHR (5,6,23). However, the exact underlying mechanisms have yet to be fully understood.…”

Section: A B C D Discussionmentioning

confidence: 99%

“…CXCL12 binds to chemokine (C-X-C motif) receptor 4 (CXCR4) and attracts a variety of cells, including resting T lymphocytes, monocytes, CD34 + stem cells and mature eosinophils (3). CXCL12 and its receptor CXCR4 have been demonstrated to be involved in Th2-type allergic airway responses, and inhibition of CXCL12 or CXCR4 leads to reduced airway inflammation and AHR (4)(5)(6). Furthermore, another study demonstrated that the levels of CXCL12 were significantly higher in bronchoalveolar lavage fluids (BALF) of asthmatic patients compared with healthy individuals, and the concentration of CXCL12 was correlated with inflammatory cell numbers in the BALF (7).…”

Section: Introductionmentioning

confidence: 99%

CXCR4 inhibitor attenuates ovalbumin-induced airway inflammation and hyperresponsiveness by inhibiting Th17 and Tc17 cell immune response

Chen

Teng

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Accumulating evidence suggests that chemokine (C-X-C motif) ligand 12 (CXCL12) and its receptor chemokine (C-X-C motif) receptor 4 (CXCR4) may contribute to the pathogenesis of allergic asthma. However, the underlying molecular mechanisms remain to be fully understood. T-helper 17 cells (Th17) and T-cytotoxic 17 cells (Tc17) have been implicated in the development of several allergic disorders, including asthma. The present study aimed to explore the association between CXCL12 signaling and Th17/Tc17 cells in the development of asthma. Ovalbumin (OVA)-sensitized BALB/c mice were treated with AMD3100, a specific CXCR4 antagonist, prior to OVA challenge. Following the final allergen (OVA) challenge, airway responsiveness to methacholine, influx of inflammatory cells to the airway, and cytokine levels in the bronchoalveolar lavage fluids (BALF) and lung homogenate were assessed. Interleukin (IL)-17-expressing CD3 + CD8 -lymphocytes (Th17 cells) and IL-17 + CD3 + CD8 + lymphocytes (Tc17 cells) isolated from lung tissue samples were detected by flow cytometry. The results of the present study demonstrated that administration of AMD3100 significantly decreased airway responsiveness to methacholine, attenuated the influx of inflammatory cells to the airway and reduced the levels of IL-4, IL-5 and IL-13 in the BALF. Furthermore, AMD3100 significantly reduced the increased number of lung Th17 and Tc17 cells as well as the levels of IL-17 in the lung homogenate induced by OVA challenge. In conclusion, the CXCR4 inhibitor suppresses the asthmatic response, which is associated with attenuation of the Th17 and Tc17 cell immune response.

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Neutraligands of C5a can potentially occlude the interaction of C5a with the complement receptors C5aR1 and C5aR2

Das

Ghosh

Gupta

et al. 2022

J of Cellular Biochemistry

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An Antedrug of the CXCL12 Neutraligand Blocks Experimental Allergic Asthma without Systemic Effect in Mice

Cited by 32 publications

References 67 publications

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

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

CXCR4 inhibitor attenuates ovalbumin-induced airway inflammation and hyperresponsiveness by inhibiting Th17 and Tc17 cell immune response

Neutraligands of C5a can potentially occlude the interaction of C5a with the complement receptors C5aR1 and C5aR2

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