Granulocyte-macrophage colony stimulating factor blockade promotes ccr9 + lymphocyte expansion in Nod2 deficient mice

Charles M. Samson, Ingrid Jurickova, Erin Molden, William Schreiner, Joshua Colliver, Erin Bonkowski, Xiaonan Han, Bruce C. Trapnell, Lee A. Denson

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Background: Ileal involvement in Crohn's disease (CD) is associated with NOD2 mutations and granulocyte-macrophage colony stimulating factor autoantibodies (GM-CSF Ab), and GM-CSF blockade promotes ileitis in Nod2/Card15-deficient (C15KO) mice. RALDH2-expressing dendritic cells (DC) and IL-4 promote CCR9 imprinting and small bowel homing of T lymphocytes, in conjunction with CCL25 expression by ileal epithelial cells (IEC). We hypothesized that GM-CSF neutralization promotes ileal disease by modulating expression of CCL25 by IEC and CCR9 by T lymphocytes via Nod2-dependent and independent pathways. Methods: CCL25 and CCR9 expression were determined in pediatric CD patients stratified by GM-CSF Ab. Ileitis was induced in C15KO mice via GM-CSF Ab administration followed by nonsteroidal antiinflammatory drug (NSAID) exposure, and expression of CCL25, CCR9, FOXP3, intracellular cytokines, and RALDH2 was determined in IEC and immune cell populations. Results: The frequency of CCL25 + IEC and CCR9 + T lymphocytes was increased in CD patients with elevated GM-CSF Ab. In the murine model, GM-CSF blockade alone induced IEC CCL25 expression, and reduced the frequency of mesenteric lymph node (MLN) CD4 +FOXP3 + cells, while Card15 deficiency alone enhanced MLN DC RALDH2 expression. Both GM-CSF neutralization and Card15 deficiency were required for downregulation of MLN DC IL-10 expression; under these conditions NSAID exposure led to an expansion of IL-4 + and IL-17 + CCR9 + lymphocytes in the ileum. Conclusions: GM-CSF prevents ileal expansion of CCR9 + lymphocytes via Nod2-dependent and independent pathways. CCR9 blockade may be beneficial in CD patients with elevated GM-CSF Ab.

Original languageEnglish
Pages (from-to)2443-2455
Number of pages13
JournalInflammatory bowel diseases
Volume17
Issue number12
DOIs
StatePublished - Dec 1 2011
Externally publishedYes

Keywords

  • CCL25
  • Crohn's disease
  • RALDH2
  • dendritic cell

Fingerprint Dive into the research topics of 'Granulocyte-macrophage colony stimulating factor blockade promotes ccr9 <sup>+</sup> lymphocyte expansion in Nod2 deficient mice'. Together they form a unique fingerprint.

  • Cite this

    Samson, C. M., Jurickova, I., Molden, E., Schreiner, W., Colliver, J., Bonkowski, E., Han, X., Trapnell, B. C., & Denson, L. A. (2011). Granulocyte-macrophage colony stimulating factor blockade promotes ccr9 + lymphocyte expansion in Nod2 deficient mice. Inflammatory bowel diseases, 17(12), 2443-2455. https://doi.org/10.1002/ibd.21672