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

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.

Cyclophilin D regulates necrosis, but not apoptosis, of murine eosinophils

“…5, E and F) and that baseline inflammatory mechanisms (Fig. 5G) were not affected, along with previous studies demonstrating the role for eosinophils and their granule proteins in the disease outcomes (13,16), supports our notion that eosinophil cytolysis is the main mechanistic link between cyclophilin D deficiency and improved disease outcomes. Future studies using cell-specific deficiency will further clarify this point.…”

“…When treated with apoptosis inducers, Ppif Ϫ/Ϫ eosinophils showed no significant difference in apoptosis or necrosis from wild-type (WT) eosinophils. Since we and others previously showed that eosinophils and eosinophil granule proteins have an important role in colitis (13,16), we tested the role of cyclophilin D in a dextran sodium sulfate (DSS)-induced colitis model. Although the baseline inflammatory parameters were comparable between WT and PPIF deficiency, Ppif Ϫ/Ϫ mice exhibited decreased clinical outcomes, as evidenced by weight loss, colon length, and histological changes, which correlated with significantly reduced eosinophil cytolysis in the colon.…”

Immunity to gastrointestinal nematode infections

“…As with IL-13, it is secreted mainly by ILC2, but functions predominantly as an eosinophil recruitment and growth factor. [79][80][81] Eosinophils, which make up only a fraction of circulating leukocytes, are relatively abundant in the intestinal tract 82 and have traditionally been associated with combating parasites. There are little data, however, to suggest that deficiency in either IL-5 or eosinophils affects the polarization of protective immunity or by extension the outcome of infection, despite that eosinophil-derived mediators can skew dendritic cells to promote type 2 immunity.…”

Interleukin 23 in IBD Pathogenesis

“…More importantly, independent studies revealed that GMCSF is required for classical EAE development in mice, especially by activating microglia or mobilizing inflammatory myeloid lineages to the inflammation site [109,110]. Studies from Fiona Powrie's lab more recently showed that IL-23-dependent production of GMCSF also contributes to the pathogenesis of colitis in naïve CD4 + T-cell transfer-and Hepaticus-induced models of murine IBD [111,112]. In both models, GMCSF was shown to promote eosinophil recruitment and activation in the colon which was needed for pathogenesis.…”