Role of Eosinophils in Intestinal Inflammation and Fibrosis in Inflammatory Bowel Disease: An Overlooked Villain?

Abstract

Eosinophils are leukocytes which reside in the gastrointestinal tract under homeostatic conditions, except for the esophagus which is normally devoid of eosinophils. Research on eosinophils has primarily focused on anti-helminth responses and type 2 immune disorders. In contrast, the search for a role of eosinophils in chronic intestinal inflammation and fibrosis has been limited. With a shift in research focus from adaptive to innate immunity and the fact that the eosinophilic granules are filled with inflammatory mediators, eosinophils are becoming a point of interest in inflammatory bowel diseases. In the current review we summarize eosinophil characteristics and recruitment as well as the current knowledge on presence, inflammatory and pro-fibrotic functions of eosinophils in inflammatory bowel disease and other chronic inflammatory conditions, and we identify research gaps which should be covered in the future.

Keywords: IBD; eosinophils; fibrosis; gastrointestinal disorders; inflammation.

Figure 1

Pluripotent hematopoeitic stem cells differentiate from the bone marrow to eosinophil progenitors in response to GM-CSF, IL-3, IL-5, a decrease in transcription factor FOG-1 and increased presence of the transcription factors GATA-1, ID2 and XBP1 (A). Under the influence of IL-5 the eosinophil progenitor will be released in the peripheral circulation and further develop into mature eosinophils in the blood (B). By the binding of the chemoattractants (eotaxin-1, eotaxin-2, eotaxin-3, MCP-3, MCP-4 and RANTES) to the chemoattractant receptors (CCR1, CCR3 and CCR4) a chemoattractant gradient is created and the mature eosinophils are recruited to the GI tract (C). The binding of the cytokines IL-4, IL-5 and IL-33, primarily produced by the Th2 cells and ILC2s, to their respective receptor (IL-4R or CD124, IL-5R or CD125 and ST2) causes eosinophil activation and subsequent degranulation releasing TGF-ß, ECP, EPX, EDN and MBP. These factors possibly influence fibroblast activation and differentiation from fibroblasts to myofibroblasts (D). This figure was created via biorender.com.

Figure 2

Upon contact with several cytokines (IL-4, IL-5, IL-13, IL-33, etc.), chemokines (eotaxin-1,2 and -3, RANTES etc.) and via tissue damage and bacterial and viral infections, eosinophils will become activated. This activation is marked by an increased surface expression of CD18, CD44, CD11b and CD11c (moderate to high expression). CD25 and CD69 are not present on inactive eosinophils, but are on active eosinophils (low and high expression respectively). CD162 and CD31 on the other hand are highly expressed on inactive eosinophils but only moderately on active eosinophils and CD62L is moderately expressed on inactive eosinophils but becomes lowly expressed once the eosinophil is activated. This figure was created via biorender.com.