The Role of the CCL2/CCR2 Axis in Mouse Mast Cell Migration In Vitro and In Vivo

Tissue-resident mast cells (MCs) are important in allergic diseases. In a mouse model of allergic airways inflammation, an increase in peribronchiolar MCs was associated with increased concentrations of the chemokine CCL2 in lung lavage. MC progenitors (MCps) arising in bone marrow (BM) are recruited to tissues by transendothelial migration, and we found that CCL2 is chemotactic for MCps in freshly isolated BM in vitro. Immature, but not mature, BM-derived MCs migrated in response to CCL2 when cultured in IL-3+stem cell factor (SCF) but not when cultured in IL-3 alone. However, the cells under both culture conditions expressed mRNA for CCR2, the receptor for CCL2, and bound the radiolabeled chemokine with similar affinities, highlighting SCF as a key mediator in coupling CCR2 to downstream events, culminating in chemotaxis. Immature BM-derived MCs from IL-3 +SCF cultures, when administered i.v., accumulated at skin sites injected with CCL2 in vivo. MCp recruitment to the allergen-sensitized/challenged lung was significantly reduced in CCR2−/− and CCL2−/− mouse strains. However, reconstitution studies of sublethally irradiated and BM-reconstituted mice indicated that BM cells and stromal elements could provide CCL2, whereas the CCR2 function resided with stromal elements rather than BM cells. These experiments revealed a new function of SCF in chemokine receptor coupling, but they suggest a complex role of the CCL2/CCR2 axis in recruiting MCps during pulmonary inflammation.

[1]  S. Kostin,et al.  Efficient homing of multipotent adult mesenchymal stem cells depends on FROUNT-mediated clustering of CCR2. , 2008, Cell stem cell.

[2]  T. Hohl,et al.  Monocyte-mediated defense against microbial pathogens. , 2008, Annual review of immunology.

[3]  K. Austen,et al.  Pulmonary CXCR2 regulates VCAM-1 and antigen-induced recruitment of mast cell progenitors , 2007, Proceedings of the National Academy of Sciences.

[4]  M. Humbert,et al.  Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. , 2007, American journal of respiratory and critical care medicine.

[5]  G. Taylor,et al.  Chemotactic action of prostaglandin E2 on mouse mast cells acting via the PGE2 receptor 3 , 2007, Proceedings of the National Academy of Sciences.

[6]  J. Zehnder,et al.  Mast cells can promote the development of multiple features of chronic asthma in mice. , 2006, The Journal of clinical investigation.

[7]  R. Flavell,et al.  Alpha-4 integrins and VCAM-1, but not MAdCAM-1, are essential for recruitment of mast cell progenitors to the inflamed lung. , 2006, Blood.

[8]  K. Akashi,et al.  Developmental checkpoints of the basophil/mast cell lineages in adult murine hematopoiesis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[9]  J. Boyce,et al.  IL-4 Regulates MEK Expression Required for Lysophosphatidic Acid-Mediated Chemokine Generation by Human Mast Cells1 , 2005, The Journal of Immunology.

[10]  I. Weissman,et al.  Identification of mast cell progenitors in adult mice. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[11]  K. Matsushima,et al.  Pivotal function for cytoplasmic protein FROUNT in CCR2-mediated monocyte chemotaxis , 2005, Nature Immunology.

[12]  S. Durham,et al.  IL-9 and c-Kit+ mast cells in allergic rhinitis during seasonal allergen exposure: effect of immunotherapy. , 2005, The Journal of allergy and clinical immunology.

[13]  J. Pachter,et al.  CCR2 expression by brain microvascular endothelial cells is critical for macrophage transendothelial migration in response to CCL2. , 2005, Microvascular research.

[14]  T. Williams,et al.  Leukotriene B4, an activation product of mast cells, is a chemoattractant for their progenitors , 2005, The Journal of experimental medicine.

[15]  C. Oliver,et al.  Identification and characterization of undifferentiated mast cells in mouse bone marrow. , 2005, Blood.

[16]  B. Rollins,et al.  From bloodjournal.hematologylibrary.org at PENN STATE UNIVERSITY on February 20, 2013. For personal use only. , 2004 .

[17]  U. Pipkorn,et al.  Phenotypic expression of proteoglycan in mast cells of the human nasal mucosa , 1988, The Histochemical Journal.

[18]  J. Marshall.  Mast-cell responses to pathogens , 2004, Nature Reviews Immunology.

[19]  B. Moore,et al.  Expression and functional implications of CCR2 expression on murine alveolar epithelial cells. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[20]  E. Raz,et al.  Accumulation of Peribronchial Mast Cells in a Mouse Model of Ovalbumin Allergen Induced Chronic Airway Inflammation: Modulation by Immunostimulatory DNA Sequences1 , 2003, The Journal of Immunology.

[21]  P. Knight,et al.  Purification and characterization of mouse mast cell proteinase‐2 and the differential expression and release of mouse mast cell proteinase‐1 and ‐2 in vivo , 2003, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[22]  P. Knight,et al.  Constitutive secretion of the granule chymase mouse mast cell protease‐1 and the chemokine, CCL2, by mucosal mast cell homologues , 2003, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[23]  A. James,et al.  Increased mast cells and neutrophils in submucosal mucous glands and mucus plugging in patients with asthma , 2002, Thorax.

[24]  I. Pavord,et al.  Mast-cell infiltration of airway smooth muscle in asthma. , 2002, The New England journal of medicine.

[25]  T. Williams,et al.  The CC Chemokine Eotaxin (CCL11) Is a Partial Agonist of CC Chemokine Receptor 2b* , 2001, The Journal of Biological Chemistry.

[26]  D. Friend,et al.  Intestinal Mast Cell Progenitors Require CD49dβ7 (α4β7 Integrin) for Tissue-specific Homing , 2001, The Journal of experimental medicine.

[27]  T. Kamijo,et al.  An Increase in Circulating Mast Cell Colony-Forming Cells in Asthma1 , 2001, The Journal of Immunology.

[28]  N. Lukacs,et al.  Stem cell factor and IgE-stimulated murine mast cells produce chemokines (CCL2, CCL17, CCL22) and express chemokine receptors , 2001, Inflammation Research.

[29]  S. Galli,et al.  Mast Cells Can Amplify Airway Reactivity and Features of Chronic Inflammation in an Asthma Model in Mice , 2000, The Journal of experimental medicine.

[30]  C. Potten,et al.  β7 integrin‐deficient mice: delayed leukocyte recruitment and attenuated protective immunity in the small intestine during enteric helminth infection , 2000, European journal of immunology.

[31]  R. Strieter,et al.  Monocyte chemoattractant protein-1 mediates cockroach allergen-induced bronchial hyperreactivity in normal but not CCR2-/- mice: the role of mast cells. , 1999, Journal of immunology.

[32]  R. Strieter,et al.  Differential monocyte chemoattractant protein-1 and chemokine receptor 2 expression by murine lung fibroblasts derived from Th1- and Th2-type pulmonary granuloma models. , 1999, Journal of immunology.

[33]  H. Miller,et al.  A novel function for transforming growth factor-beta1: upregulation of the expression and the IgE-independent extracellular release of a mucosal mast cell granule-specific beta-chymase, mouse mast cell protease-1. , 1999, Blood.

[34]  C. Martínez-A,et al.  The Coordinated Action of CC Chemokines in the Lung Orchestrates Allergic Inflammation and Airway Hyperresponsiveness , 1998, The Journal of experimental medicine.

[35]  B. Rollins,et al.  Abnormalities in Monocyte Recruitment and Cytokine Expression in Monocyte Chemoattractant Protein 1–deficient Mice , 1998, The Journal of experimental medicine.

[36]  Michael R. Müller,et al.  The c-kit ligand stem cell factor and anti-IgE promote expression of monocyte chemoattractant protein-1 in human lung mast cells. , 1997, Blood.

[37]  S. Holgate,et al.  Release of RANTES, MIP-1 alpha, and MCP-1 into asthmatic airways following endobronchial allergen challenge. , 1997, American journal of respiratory and critical care medicine.

[38]  R. Strieter,et al.  Differential recruitment of leukocyte populations and alteration of airway hyperreactivity by C-C family chemokines in allergic airway inflammation. , 1997, Journal of immunology.

[39]  D. Friend,et al.  Mast cells that reside at different locations in the jejunum of mice infected with Trichinella spiralis exhibit sequential changes in their granule ultrastructure and chymase phenotype , 1996, The Journal of cell biology.

[40]  P. Forsythe,et al.  Increased MCP-1, RANTES, and MIP-1alpha in bronchoalveolar lavage fluid of allergic asthmatic patients. , 1996, American journal of respiratory and critical care medicine.

[41]  S. Galli,et al.  Identification of a Committed Precursor for the Mast Cell Lineage , 1996, Science.

[42]  D. Baltimore,et al.  Tissue-regulated differentiation and maturation of a v-abl-immortalized mast cell-committed progenitor. , 1995, Immunity.

[43]  D. Taub,et al.  Bone marrow-derived murine mast cells migrate, but do not degranulate, in response to chemokines. , 1995, Journal of immunology.

[44]  D. Friend,et al.  Mouse bone marrow-derived mast cells (mBMMC) obtained in vitro from mice that are mast cell-deficient in vivo express the same panel of granule proteases as mBMMC and serosal mast cells from their normal littermates , 1994, The Journal of experimental medicine.

[45]  W. Fokkens,et al.  Dynamics of mast cells in the nasal mucosa of patients with allergic rhinitis and non‐allergic controls: a biopsy study , 1992, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[46]  J. Schrader,et al.  Frequency of mast cell precursors in normal tissues determined by an in vitro assay: antigen induces parallel increases in the frequency of P cell precursors and mast cells. , 1983, Journal of immunology.

[47]  J. Bienenstock,et al.  Immunologically mediated intestinal mastocytosis in Nippostrongylus brasiliensis-infected rats. , 1979, Immunology.

[48]  Y. Kitamura,et al.  Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation. , 1978, Blood.