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CX₃CL1 (fractalkine) and its receptor CX₃CR1 regulate atopic dermatitis by controlling effector T cell retention in inflamed skin.

Staumont-Sallé D, Fleury S, Lazzari A, Molendi-Coste O, Hornez N, Lavogiez C, Kanda A, Wartelle J, Fries A, Pennino D, Mionnet C, Prawitt J, Bouchaert E, Delaporte E, Glaichenhaus N, Staels B, Julia V, Dombrowicz D - J. Exp. Med. (2014)

Bottom Line: CX3CR1 deficiency affected neither antigen presentation nor T cell proliferation in vivo upon skin sensitization, but CX3CR1 expression by both Th2 and Th1 cells was required to induce AD.Surprisingly, unlike in allergic asthma, where CX3CL1 and CX3CR1 regulate the pathology by controlling effector CD4(+) T cell survival within inflamed tissues, adoptive transfer experiments established CX3CR1 as a key regulator of CD4(+) T cell retention in inflamed skin, indicating a new function for this chemokine receptor.Therefore, although CX3CR1 and CX3CL1 act through distinct mechanisms in different pathologies, our results further indicate their interest as promising therapeutic targets in allergic diseases.

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Affiliation: Institut National de la Santé et de la Recherche Médicale U1011, Institut Pasteur de Lille and Université Lille 2, 59019 Lille, FranceInstitut National de la Santé et de la Recherche Médicale U1011, Institut Pasteur de Lille and Université Lille 2, 59019 Lille, FranceInstitut National de la Santé et de la Recherche Médicale U1011, Institut Pasteur de Lille and Université Lille 2, 59019 Lille, France European Genomic Institute of Diabetes, 59045 Lille, France Department of Dermatology, Claude-Huriez Hospital, 59037 Lille, France.

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Abrogation of AD features in WT mice treated with CX3-AT. (A) Timeline of CX3-AT administration during AD induction. (B) Epidermal thickness. (C) Eosinophil, mast cell, MHC II+, and CD4+ T cell numbers in dermis. (D) AHR to increasing methacholine concentrations. Resistance was evaluated by invasive plethysmography. (E) Lung inflammatory response: total number of cells, macrophages, neutrophils, lymphocytes, and eosinophils in BALF. Data are expressed as mean ± SEM (n = 6–10 animals per group). One out of two independent experiments is shown for each panel. Statistically different from PBS-treated mice: *, P < 0.05; and **, P < 0.01; statistically different from vehicle-treated mice: $, P < 0.05.
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fig2: Abrogation of AD features in WT mice treated with CX3-AT. (A) Timeline of CX3-AT administration during AD induction. (B) Epidermal thickness. (C) Eosinophil, mast cell, MHC II+, and CD4+ T cell numbers in dermis. (D) AHR to increasing methacholine concentrations. Resistance was evaluated by invasive plethysmography. (E) Lung inflammatory response: total number of cells, macrophages, neutrophils, lymphocytes, and eosinophils in BALF. Data are expressed as mean ± SEM (n = 6–10 animals per group). One out of two independent experiments is shown for each panel. Statistically different from PBS-treated mice: *, P < 0.05; and **, P < 0.01; statistically different from vehicle-treated mice: $, P < 0.05.

Mentions: To further confirm the key role of CX3CR1 in AD development, we next investigated whether inhibition of CX3CL1–CX3CR1 interactions would inhibit the pathology in WT animals. We investigated the efficacy of a CX3CR1 antagonist (CX3-AT), whose potency was already validated in an allergic asthma model (Mionnet et al., 2010), using prophylactic or therapeutic administration protocols (Fig. 2 A). Both administration schedules fully inhibited antigen-induced epidermal thickening (Fig. 2 B), as well as dermal mast cell, eosinophil, and CD4+ T cell infiltration (Fig. 2 C). Upon LACK aerosol challenge, AHR and inflammatory cell infiltration in the airways were also significantly decreased upon both prophylactic and therapeutic treatments (Fig. 2, C and D). Collectively, these results confirm the key role of CX3CR1–CX3CL1 in AD in nongenetically manipulated mice and further demonstrate that pharmacological inhibition of CX3CL1–CX3CR1 interactions abrogate skin and lung inflammation.


CX₃CL1 (fractalkine) and its receptor CX₃CR1 regulate atopic dermatitis by controlling effector T cell retention in inflamed skin.

Staumont-Sallé D, Fleury S, Lazzari A, Molendi-Coste O, Hornez N, Lavogiez C, Kanda A, Wartelle J, Fries A, Pennino D, Mionnet C, Prawitt J, Bouchaert E, Delaporte E, Glaichenhaus N, Staels B, Julia V, Dombrowicz D - J. Exp. Med. (2014)

Abrogation of AD features in WT mice treated with CX3-AT. (A) Timeline of CX3-AT administration during AD induction. (B) Epidermal thickness. (C) Eosinophil, mast cell, MHC II+, and CD4+ T cell numbers in dermis. (D) AHR to increasing methacholine concentrations. Resistance was evaluated by invasive plethysmography. (E) Lung inflammatory response: total number of cells, macrophages, neutrophils, lymphocytes, and eosinophils in BALF. Data are expressed as mean ± SEM (n = 6–10 animals per group). One out of two independent experiments is shown for each panel. Statistically different from PBS-treated mice: *, P < 0.05; and **, P < 0.01; statistically different from vehicle-treated mice: $, P < 0.05.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4042636&req=5

fig2: Abrogation of AD features in WT mice treated with CX3-AT. (A) Timeline of CX3-AT administration during AD induction. (B) Epidermal thickness. (C) Eosinophil, mast cell, MHC II+, and CD4+ T cell numbers in dermis. (D) AHR to increasing methacholine concentrations. Resistance was evaluated by invasive plethysmography. (E) Lung inflammatory response: total number of cells, macrophages, neutrophils, lymphocytes, and eosinophils in BALF. Data are expressed as mean ± SEM (n = 6–10 animals per group). One out of two independent experiments is shown for each panel. Statistically different from PBS-treated mice: *, P < 0.05; and **, P < 0.01; statistically different from vehicle-treated mice: $, P < 0.05.
Mentions: To further confirm the key role of CX3CR1 in AD development, we next investigated whether inhibition of CX3CL1–CX3CR1 interactions would inhibit the pathology in WT animals. We investigated the efficacy of a CX3CR1 antagonist (CX3-AT), whose potency was already validated in an allergic asthma model (Mionnet et al., 2010), using prophylactic or therapeutic administration protocols (Fig. 2 A). Both administration schedules fully inhibited antigen-induced epidermal thickening (Fig. 2 B), as well as dermal mast cell, eosinophil, and CD4+ T cell infiltration (Fig. 2 C). Upon LACK aerosol challenge, AHR and inflammatory cell infiltration in the airways were also significantly decreased upon both prophylactic and therapeutic treatments (Fig. 2, C and D). Collectively, these results confirm the key role of CX3CR1–CX3CL1 in AD in nongenetically manipulated mice and further demonstrate that pharmacological inhibition of CX3CL1–CX3CR1 interactions abrogate skin and lung inflammation.

Bottom Line: CX3CR1 deficiency affected neither antigen presentation nor T cell proliferation in vivo upon skin sensitization, but CX3CR1 expression by both Th2 and Th1 cells was required to induce AD.Surprisingly, unlike in allergic asthma, where CX3CL1 and CX3CR1 regulate the pathology by controlling effector CD4(+) T cell survival within inflamed tissues, adoptive transfer experiments established CX3CR1 as a key regulator of CD4(+) T cell retention in inflamed skin, indicating a new function for this chemokine receptor.Therefore, although CX3CR1 and CX3CL1 act through distinct mechanisms in different pathologies, our results further indicate their interest as promising therapeutic targets in allergic diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale U1011, Institut Pasteur de Lille and Université Lille 2, 59019 Lille, FranceInstitut National de la Santé et de la Recherche Médicale U1011, Institut Pasteur de Lille and Université Lille 2, 59019 Lille, FranceInstitut National de la Santé et de la Recherche Médicale U1011, Institut Pasteur de Lille and Université Lille 2, 59019 Lille, France European Genomic Institute of Diabetes, 59045 Lille, France Department of Dermatology, Claude-Huriez Hospital, 59037 Lille, France.

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Related in: MedlinePlus