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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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Absence of AD and attenuation of associated humoral and lung inflammatory response in CX3CR1-deficient mice. AD was induced on abdominal skin in CX3CR1+/+ and CX3CR1gfp/gfp mice by epicutaneous LACK sensitization for three 1-wk periods, with a 2-wk interval between applications. At day 49, sera were collected and animals were challenged by LACK nebulization. At day 50, AHR to increasing concentrations of methacholine was measured by invasive plethysmography. Then, mice were sacrificed and BALF was collected and analyzed on cytospin preparations. Skin samples were collected at the site of sensitization. (A) May-Grünwald Giemsa staining of skin sections. Black arrows indicate mast cells and, in the inset, eosinophils. (B) Epidermal thickness. (C) Eosinophil, mast cell, MHC II+, and CD4+ T cell numbers in dermis. (D) Ig concentrations in serum. Total IgE (left), LACK-specific IgG1 (middle), and LACK-specific IgG2a (right) concentrations are shown. Horizontal bars indicate mean. (E) AHR to increasing methacholine concentrations. Resistance was evaluated by invasive plethysmography. (F) 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. *, P < 0.05; ** P < 0.01.
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fig1: Absence of AD and attenuation of associated humoral and lung inflammatory response in CX3CR1-deficient mice. AD was induced on abdominal skin in CX3CR1+/+ and CX3CR1gfp/gfp mice by epicutaneous LACK sensitization for three 1-wk periods, with a 2-wk interval between applications. At day 49, sera were collected and animals were challenged by LACK nebulization. At day 50, AHR to increasing concentrations of methacholine was measured by invasive plethysmography. Then, mice were sacrificed and BALF was collected and analyzed on cytospin preparations. Skin samples were collected at the site of sensitization. (A) May-Grünwald Giemsa staining of skin sections. Black arrows indicate mast cells and, in the inset, eosinophils. (B) Epidermal thickness. (C) Eosinophil, mast cell, MHC II+, and CD4+ T cell numbers in dermis. (D) Ig concentrations in serum. Total IgE (left), LACK-specific IgG1 (middle), and LACK-specific IgG2a (right) concentrations are shown. Horizontal bars indicate mean. (E) AHR to increasing methacholine concentrations. Resistance was evaluated by invasive plethysmography. (F) 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. *, P < 0.05; ** P < 0.01.

Mentions: To assess the contribution of CX3CR1 to AD development, we used a previously described model of AD based on repeated epicutaneous sensitizations (Spergel et al., 1998) with Leishmania major–activated C kinase (LACK) as antigen and compared the response of CX3CR1-deficient (gfp/gfp) mice, in which the CX3CR1 gene has been replaced by GFP (Jung et al., 2000), with that from their proficient (+/+) WT counterparts. Neither strain exhibited an inflammatory phenotype in the absence of LACK sensitization (Fig. 1 A). Compared with vehicle (i.e., PBS)-sensitized CX3CR1+/+ mice, LACK-sensitized CX3CR1+/+ mice exhibited a significant skin inflammatory response, characterized by a 50% increase in epidermal thickening (Fig. 1 B) associated with more pronounced hyperkeratosis, spongiosis, and dermal cellular infiltrates, including mast cells, eosinophils, MHC-II+, and CD4+ T cells (Fig. 1 C), as well as increased skin and inguinal LN expression of inflammatory and Th1- and Th2-associated cytokines, chemokines, and chemokine receptors (not depicted). In sharp contrast, CX3CR1gfp/gfp mice did not develop a skin inflammatory response upon LACK sensitization (Fig. 1, A and B). Compared with PBS-sensitized CX3CR1gfp/gfp mice, only MHC-II+ cell numbers were increased, but to a lesser extent than in LACK-sensitized CX3CR1+/+ animals (Fig. 1 C). Furthermore, expression of Th1 and inflammatory response genes was also significantly decreased (not depicted). Humoral response was also altered in CX3CR1gfp/gfp compared with CX3CR1+/+ mice, with decreased total Th2-associated IgE concentrations (but not IgG1 titers), as well as decreased Th1-associated antigen-specific IgG2a titers (Fig. 1 D).


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)

Absence of AD and attenuation of associated humoral and lung inflammatory response in CX3CR1-deficient mice. AD was induced on abdominal skin in CX3CR1+/+ and CX3CR1gfp/gfp mice by epicutaneous LACK sensitization for three 1-wk periods, with a 2-wk interval between applications. At day 49, sera were collected and animals were challenged by LACK nebulization. At day 50, AHR to increasing concentrations of methacholine was measured by invasive plethysmography. Then, mice were sacrificed and BALF was collected and analyzed on cytospin preparations. Skin samples were collected at the site of sensitization. (A) May-Grünwald Giemsa staining of skin sections. Black arrows indicate mast cells and, in the inset, eosinophils. (B) Epidermal thickness. (C) Eosinophil, mast cell, MHC II+, and CD4+ T cell numbers in dermis. (D) Ig concentrations in serum. Total IgE (left), LACK-specific IgG1 (middle), and LACK-specific IgG2a (right) concentrations are shown. Horizontal bars indicate mean. (E) AHR to increasing methacholine concentrations. Resistance was evaluated by invasive plethysmography. (F) 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. *, P < 0.05; ** P < 0.01.
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fig1: Absence of AD and attenuation of associated humoral and lung inflammatory response in CX3CR1-deficient mice. AD was induced on abdominal skin in CX3CR1+/+ and CX3CR1gfp/gfp mice by epicutaneous LACK sensitization for three 1-wk periods, with a 2-wk interval between applications. At day 49, sera were collected and animals were challenged by LACK nebulization. At day 50, AHR to increasing concentrations of methacholine was measured by invasive plethysmography. Then, mice were sacrificed and BALF was collected and analyzed on cytospin preparations. Skin samples were collected at the site of sensitization. (A) May-Grünwald Giemsa staining of skin sections. Black arrows indicate mast cells and, in the inset, eosinophils. (B) Epidermal thickness. (C) Eosinophil, mast cell, MHC II+, and CD4+ T cell numbers in dermis. (D) Ig concentrations in serum. Total IgE (left), LACK-specific IgG1 (middle), and LACK-specific IgG2a (right) concentrations are shown. Horizontal bars indicate mean. (E) AHR to increasing methacholine concentrations. Resistance was evaluated by invasive plethysmography. (F) 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. *, P < 0.05; ** P < 0.01.
Mentions: To assess the contribution of CX3CR1 to AD development, we used a previously described model of AD based on repeated epicutaneous sensitizations (Spergel et al., 1998) with Leishmania major–activated C kinase (LACK) as antigen and compared the response of CX3CR1-deficient (gfp/gfp) mice, in which the CX3CR1 gene has been replaced by GFP (Jung et al., 2000), with that from their proficient (+/+) WT counterparts. Neither strain exhibited an inflammatory phenotype in the absence of LACK sensitization (Fig. 1 A). Compared with vehicle (i.e., PBS)-sensitized CX3CR1+/+ mice, LACK-sensitized CX3CR1+/+ mice exhibited a significant skin inflammatory response, characterized by a 50% increase in epidermal thickening (Fig. 1 B) associated with more pronounced hyperkeratosis, spongiosis, and dermal cellular infiltrates, including mast cells, eosinophils, MHC-II+, and CD4+ T cells (Fig. 1 C), as well as increased skin and inguinal LN expression of inflammatory and Th1- and Th2-associated cytokines, chemokines, and chemokine receptors (not depicted). In sharp contrast, CX3CR1gfp/gfp mice did not develop a skin inflammatory response upon LACK sensitization (Fig. 1, A and B). Compared with PBS-sensitized CX3CR1gfp/gfp mice, only MHC-II+ cell numbers were increased, but to a lesser extent than in LACK-sensitized CX3CR1+/+ animals (Fig. 1 C). Furthermore, expression of Th1 and inflammatory response genes was also significantly decreased (not depicted). Humoral response was also altered in CX3CR1gfp/gfp compared with CX3CR1+/+ mice, with decreased total Th2-associated IgE concentrations (but not IgG1 titers), as well as decreased Th1-associated antigen-specific IgG2a titers (Fig. 1 D).

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