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

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.

• Authors: Charles M Samson, Ingrid Jurickova, Erin Molden, William Schreiner, Joshua Colliver, Erin Bonkowski, Xiaonan Han, Bruce C Trapnell, Lee A Denson
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 17 Issue 12 Pg. 2443-55 (Dec 2011) ISSN: 1536-4844 [Electronic] England
• PMID: 21381154 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Crohn's & Crohn's & Colitis Foundation of America, Inc.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• CC chemokine receptor 9
• CCL25 protein, human
• Chemokines, CC
• Nod2 Signaling Adaptor Protein
• Nod2 protein, mouse
• RNA, Messenger
• Receptors, CCR
• Interleukin-10
• Granulocyte-Macrophage Colony-Stimulating Factor
• Aldehyde Oxidoreductases
• RALDH2 protein, mouse

Topics

• Aldehyde Oxidoreductases (genetics, metabolism)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Chemokines, CC (genetics, metabolism)
• Child
• Crohn Disease (immunology, metabolism, pathology)
• Dendritic Cells (drug effects, immunology, metabolism)
• Disease Models, Animal
• Female
• Flow Cytometry
• Granulocyte-Macrophage Colony-Stimulating Factor (antagonists & inhibitors, metabolism)
• Humans
• Ileitis (immunology, metabolism, pathology)
• Immunoenzyme Techniques
• Interleukin-10 (genetics, metabolism)
• Lymphocytes (immunology, metabolism, pathology)
• Male
• Mice
• Mice, Knockout
• Mutation (genetics)
• Nod2 Signaling Adaptor Protein (physiology)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Receptors, CCR (genetics, metabolism)