Granulocyte Macrophage Colony-Stimulating Factor-Activated Eosinophils Promote Interleukin-23 Driven Chronic Colitis

The role of intestinal eosinophils in immune homeostasis is enigmatic and the molecular signals that drive them from protective to tissue damaging are unknown. Most commonly associated with Th2 cell-mediated diseases, we describe a role for eosinophils as crucial effectors of the interleukin-23 (IL-...

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Published in:	Immunity (Cambridge, Mass.) Mass.), 2015-07, Vol.43 (1), p.187-199
Main Authors:	Griseri, Thibault, Arnold, Isabelle C., Pearson, Claire, Krausgruber, Thomas, Schiering, Chris, Franchini, Fanny, Schulthess, Julie, McKenzie, Brent S., Crocker, Paul R., Powrie, Fiona
Format:	Article
Language:	eng
Subjects:	Animals Cell Movement - immunology Colitis - immunology Colon Cytokine Receptor Common beta Subunit - genetics Cytokines Eosinophil Peroxidase - secretion Eosinophils - immunology Gene expression Granulocyte-Macrophage Colony-Stimulating Factor - antagonists & inhibitors Granulocyte-Macrophage Colony-Stimulating Factor - immunology Inflammation Inflammation - immunology Inflammatory bowel disease Interleukin-23 Subunit p19 - immunology Interleukin-5 - antagonists & inhibitors Intestines - cytology Intestines - immunology Intestines - pathology Leukocyte Reduction Procedures Lung diseases Lymphocytes Mice Mice, Inbred C57BL Mice, Knockout Neutrophils - immunology Rodents Statistical analysis Tumor Necrosis Factors - secretion
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Summary:	The role of intestinal eosinophils in immune homeostasis is enigmatic and the molecular signals that drive them from protective to tissue damaging are unknown. Most commonly associated with Th2 cell-mediated diseases, we describe a role for eosinophils as crucial effectors of the interleukin-23 (IL-23)-granulocyte macrophage colony-stimulating factor (GM-CSF) axis in colitis. Chronic intestinal inflammation was characterized by increased bone marrow eosinopoiesis and accumulation of activated intestinal eosinophils. IL-5 blockade or eosinophil depletion ameliorated colitis, implicating eosinophils in disease pathogenesis. GM-CSF was a potent activator of eosinophil effector functions and intestinal accumulation, and GM-CSF blockade inhibited chronic colitis. By contrast neutrophil accumulation was GM-CSF independent and dispensable for colitis. In addition to TNF secretion, release of eosinophil peroxidase promoted colitis identifying direct tissue-toxic mechanisms. Thus, eosinophils are key perpetrators of chronic inflammation and tissue damage in IL-23-mediated immune diseases and it suggests the GM-CSF-eosinophil axis as an attractive therapeutic target. [Display omitted] •GM-CSF synergizes with IL-5 to exacerbate eosinopoiesis during chronic colitis•GM-CSF-activated eosinophils promote IL-23 driven colitis•Depletion of eosinophils, but not of neutrophils, dampens colitis•GM-CSF increases eosinophil production of inflammatory cytokines TNF and IL-13 Although eosinophils are most commonly associated with Th2-cell-mediated diseases, Powrie and colleagues describe a crucial role for eosinophils in IL-23-mediated chronic colitis. GM-CSF was a potent activator of eosinopoiesis and concomitant accumulation of activated and tissue-toxic eosinophils in the inflamed intestine, as well as their secretion of inflammatory cytokines.
ISSN:	1074-7613 1097-4180