Impaired mast cell maturation and degranulation and attenuated allergic responses in Ndrg1-deficient mice

J Immunol. 2007 Jun 1;178(11):7042-53. doi: 10.4049/jimmunol.178.11.7042.

Abstract

We have previously reported that N-myc downstream regulated gene-1 (NDRG1) is an early inducible protein during the maturation of mouse bone marrow-derived mast cells (BMMCs) toward a connective tissue mast cell-like phenotype. To clarify the function of NDRG1 in mast cells and allergic responses, we herein analyzed mast cell-associated phenotypes of mice lacking the Ndrg1 gene. Allergic responses including IgE-mediated passive systemic and cutaneous anaphylactic reactions were markedly attenuated in Ndrg1-deficient mice as compared with those in wild-type mice. In Ndrg1-deficient mice, dermal and peritoneal mast cells were decreased in number and morphologically abnormal with impaired degranulating ability. Ex vivo, Ndrg1-deficient BMMCs cocultured with Swiss 3T3 fibroblasts in the presence of stem cell factor, a condition that facilitates the maturation of BMMCs toward a CTMC-like phenotype, displayed less exocytosis than replicate wild-type cells after the cross-linking of FcepsilonRI or stimulation with compound 48/80, even though the exocytotic response of IL-3-maintained, immature BMMCs from both genotypes was comparable. Unlike degranulation, the production of leukotriene and cytokines by cocultured BMMCs was unaffected by NDRG1 deficiency. Taken together, the altered phenotypes of Ndrg1-deficient mast cells both in vivo and ex vivo suggest that NDRG1 has roles in the terminal maturation and effector function (degranulation) of mast cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphylaxis / genetics*
  • Anaphylaxis / immunology*
  • Anaphylaxis / pathology
  • Animals
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / physiology
  • Cell Degranulation / genetics
  • Cell Degranulation / immunology*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cells, Cultured
  • Coculture Techniques
  • Cytoplasmic Granules / genetics
  • Cytoplasmic Granules / immunology
  • Cytoplasmic Granules / pathology
  • Exocytosis / genetics
  • Exocytosis / immunology
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Immunophenotyping
  • Intracellular Signaling Peptides and Proteins / deficiency*
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / physiology
  • Mast Cells / immunology*
  • Mast Cells / metabolism
  • Mast Cells / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Passive Cutaneous Anaphylaxis / genetics
  • Passive Cutaneous Anaphylaxis / immunology

Substances

  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • N-myc downstream-regulated gene 1 protein