Abstract
SummaryThe 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.
Highlights
Chronic intestinal inflammation is characterized by dysregulated T helper 1 (Th1) and Th17 cell and innate lymphoid cell responses with excessive production of inflammatory cytokines (Maloy and Powrie, 2011), leading to increased production of granulocyte-monocyte progenitors (GMPs) and accumulation of inflammatory myeloid cells in the target tissue (Griseri et al, 2012)
We found both populations among colonic lamina propria leukocytes, with high granularity (SSChi) and expression of the eotaxin receptor CCR3 confirming them as eosinophils (Figures 1A and S1A)
The abundance of intestinal eosinophils was confirmed in situ, with a high density of Siglec-F+ cells observed in inflamed colons (Figure S1E)
Summary
Chronic intestinal inflammation is characterized by dysregulated T helper 1 (Th1) and Th17 cell and innate lymphoid cell responses with excessive production of inflammatory cytokines (Maloy and Powrie, 2011), leading to increased production of granulocyte-monocyte progenitors (GMPs) and accumulation of inflammatory myeloid cells in the target tissue (Griseri et al, 2012). Eosinophils, which arise from GMPs through an eosinophil progenitor (EoP) intermediate (Iwasaki et al, 2005), are rare in the blood but more abundant in tissues such as the gastrointestinal tract, their contribution to intestinal homeostasis remains enigmatic (Kita, 2011; Mishra et al, 1999). Beyond their role in Th2 cell immunity, eosinophil secrete various inflammatory mediators (e.g., TNF, IL-13, CXCL1) and have been implicated in activation of dendritic cells (DCs) and neutrophils (Rosenberg et al, 2013). They can release anti-microbial compounds toxic for viruses and bacteria and promote the survival of immunoglobulin A (IgA)-secreting plasma cells in the intestine, suggesting a possible anti-microbial function (Chu et al, 2014; Rosenberg et al, 2013)
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