Murine CXCL14 Is Dispensable for Dendritic Cell Function and Localization within Peripheral Tissues

ABSTRACT Dendritic cells (DCs) have long been recognized as key regulators of immune responses. However, the process of their recruitment to peripheral tissues and turnover during homeostasis remains largely unknown. The chemokine CXCL14 (BRAK) is constitutively expressed in skin and other epithelial tissues. Recently, the human chemokine was proposed to play a role in the homeostatic recruitment of macrophage and/or DC precursors toward the periphery, such as skin. Although so far no physiological function could be demonstrated for the murine CXCL14, it shows a remarkable homology to the human chemokine. In order to elucidate the in vivo role of CXCL14, we generated a mouse defective for this chemokine. We studied various components of the immune system with emphasis on monocytes/macrophages and DC/Langerhans cell (LC) populations in different tissues during steady state but did not find a significant difference between knockout (CXCL14−/−) and control mice. Functionally, LCs were able to become activated, to migrate out of skin, and to elicit a delayed type of hypersensitivity reaction. Overall, our data indicate that murine CXCL14 is dispensable for the homeostatic recruitment of antigen-presenting cells toward the periphery and for LC functionality.

[1]  E. Kubota,et al.  BRAK/CXCL14 expression suppresses tumor growth in vivo in human oral carcinoma cells. , 2006, Biochemical and biophysical research communications.

[2]  R. Ferris,et al.  Loss of new chemokine CXCL14 in tumor tissue is associated with low infiltration by dendritic cells (DC), while restoration of human CXCL14 expression in tumor cells causes attraction of DC both in vitro and in vivo. , 2006, The Journal of Immunology.

[3]  B. Malissen,et al.  Langerhans cells--revisiting the paradigm using genetically engineered mice. , 2006, Trends in immunology.

[4]  F. Ginhoux,et al.  Langerhans cells arise from monocytes in vivo , 2006, Nature Immunology.

[5]  S. Gordon,et al.  Monocyte and macrophage heterogeneity , 2005, Nature Reviews Immunology.

[6]  Lisa M. Ebert,et al.  Cutaneous CXCL14 targets blood precursors to epidermal niches for Langerhans cell differentiation. , 2005, Immunity.

[7]  W. Isaacs,et al.  Modulation of CXCL14 (BRAK) expression in prostate cancer , 2005, The Prostate.

[8]  P. Perrin,et al.  Dynamics and function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells. , 2005, Immunity.

[9]  F. Carraro,et al.  Role of inflammatory mediators in angiogenesis. , 2005, Current drug targets. Inflammation and allergy.

[10]  Hidde L Ploegh,et al.  CX3CR1-Mediated Dendritic Cell Access to the Intestinal Lumen and Bacterial Clearance , 2005, Science.

[11]  A. El‐Naggar,et al.  BRAK/CXCL14 Is a Potent Inhibitor of Angiogenesis and a Chemotactic Factor for Immature Dendritic Cells , 2004, Cancer Research.

[12]  M. Rosenkilde,et al.  The chemokine system – a major regulator of angiogenesis in health and disease , 2004, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[13]  N. Van Rooijen,et al.  Subpopulations of Mouse Blood Monocytes Differ in Maturation Stage and Inflammatory Response1 , 2004, The Journal of Immunology.

[14]  P. Iribarren,et al.  Chemokines and chemokine receptors: their manifold roles in homeostasis and disease. , 2004, Cellular & molecular immunology.

[15]  Marlene Wolf,et al.  Chemokines: multiple levels of leukocyte migration control. , 2004, Trends in immunology.

[16]  N. Romani,et al.  Langerhans cells – dendritic cells of the epidermis , 2003, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[17]  H. Stein,et al.  Systemic immunoregulatory and pathogenic functions of homeostatic chemokine receptors , 2002, Journal of leukocyte biology.

[18]  A. Zlotnik,et al.  Chemokines: agents for the immunotherapy of cancer? , 2002, Nature Reviews Immunology.

[19]  Yong‐jun Liu,et al.  Mouse and human dendritic cell subtypes , 2002, Nature Reviews Immunology.

[20]  A. Proudfoot Chemokine receptors: multifaceted therapeutic targets , 2002, Nature Reviews Immunology.

[21]  C. Caux,et al.  Sequential involvement of CCR2 and CCR6 ligands for immature dendritic cell recruitment: possible role at inflamed epithelial surfaces , 2002, European journal of immunology.

[22]  Simon C Watkins,et al.  Dermal-resident CD14+ cells differentiate into Langerhans cells , 2001, Nature Immunology.

[23]  M. Gunn,et al.  Cd11c+B220+Gr-1+ Cells in Mouse Lymph Nodes and Spleen Display Characteristics of Plasmacytoid Dendritic Cells , 2001, The Journal of experimental medicine.

[24]  I. Kurth,et al.  Monocyte Selectivity and Tissue Localization Suggests a Role for Breast and Kidney–Expressed Chemokine (Brak) in Macrophage Development , 2001, The Journal of experimental medicine.

[25]  C. Benoist,et al.  The Dendritic Cell Populations of Mouse Lymph Nodes1 , 2001, The Journal of Immunology.

[26]  C. Martínez-A,et al.  CCR6-deficient mice have impaired leukocyte homeostasis and altered contact hypersensitivity and delayed-type hypersensitivity responses. , 2001, The Journal of clinical investigation.

[27]  Bernhard Moser,et al.  Lymphocyte traffic control by chemokines , 2001, Nature Immunology.

[28]  F. Sallusto,et al.  Understanding dendritic cell and T‐lymphocyte traffic through the analysis of chemokine receptor expression , 2000, Immunological reviews.

[29]  C. Caux,et al.  Macrophage Inflammatory Protein 3α Is Expressed at Inflamed Epithelial Surfaces and Is the Most Potent Chemokine Known in Attracting Langerhans Cell Precursors , 2000, The Journal of experimental medicine.

[30]  M. Detmar,et al.  Thrombospondin‐1 suppresses wound healing and granulation tissue formation in the skin of transgenic mice , 2000, The EMBO journal.

[31]  C. Caux,et al.  Up-Regulation of Macrophage Inflammatory Protein-3α/CCL20 and CC Chemokine Receptor 6 in Psoriasis1 , 2000, The Journal of Immunology.

[32]  A. Sher,et al.  Analysis of Fractalkine Receptor CX3CR1 Function by Targeted Deletion and Green Fluorescent Protein Reporter Gene Insertion , 2000, Molecular and Cellular Biology.

[33]  A. Sahin,et al.  In vivo expression of the novel CXC chemokine BRAK in normal and cancerous human tissue. , 2000, The American journal of pathology.

[34]  H. Greenberg,et al.  CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue. , 2000, Immunity.

[35]  J. Watson,et al.  B cell- and monocyte-activating chemokine (BMAC), a novel non-ELR α-chemokine , 2000 .

[36]  E. Kriehuber,et al.  Macrophage Inflammatory Protein 3α Is Involved in the Constitutive Trafficking of Epidermal Langerhans Cells , 1999, The Journal of experimental medicine.

[37]  B. Ryffel,et al.  Migration of Langerhans cells and dermal dendritic cells in skin organ cultures: augmentation by TNF‐α and IL‐1 β , 1999, Journal of leukocyte biology.

[38]  H. Saeki,et al.  Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. , 1999, Journal of immunology.

[39]  H. Nakshatri,et al.  Cloning of BRAK, a novel divergent CXC chemokine preferentially expressed in normal versus malignant cells. , 1999, Biochemical and biophysical research communications.

[40]  F. Anjuère,et al.  Definition of dendritic cell subpopulations present in the spleen, Peyer's patches, lymph nodes, and skin of the mouse. , 1999, Blood.

[41]  J. Smolle,et al.  Entry into afferent lymphatics and maturation in situ of migrating murine cutaneous dendritic cells. , 1998, The Journal of investigative dermatology.

[42]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[43]  I. Kimber,et al.  α6 Integrins Are Required for Langerhans Cell Migration from the Epidermis , 1997, The Journal of experimental medicine.

[44]  G. Schuler,et al.  An improved isolation method for murine migratory cutaneous dendritic cells. , 1996, Journal of immunological methods.

[45]  P. Morris,et al.  Dendritic cell loss from nonlymphoid tissues after systemic administration of lipopolysaccharide, tumor necrosis factor, and interleukin 1 , 1995, The Journal of experimental medicine.

[46]  R. Clark Biology of dermal wound repair. , 1993, Dermatologic clinics.

[47]  R. Steinman,et al.  Migration and maturation of Langerhans cells in skin transplants and explants , 1990, The Journal of experimental medicine.

[48]  B. Moser,et al.  Chemokines , 2005, Immunologic research.

[49]  A. Enk,et al.  Dendritic cells: key cells for the induction of regulatory T cells? , 2005, Current topics in microbiology and immunology.

[50]  I. Weissman,et al.  Langerhans cells renew in the skin throughout life under steady-state conditions , 2003, Nature Immunology.

[51]  C Caux,et al.  Immunobiology of dendritic cells. , 2000, Annual review of immunology.

[52]  J. Watson,et al.  B cell- and monocyte-activating chemokine (BMAC), a novel non-ELR alpha-chemokine. , 2000, International immunology.