Roles and regulation of gastrointestinal eosinophils in immunity and disease

Abstract

Eosinophils have historically been considered to be destructive end-stage effector cells that have a role in parasitic infections and allergic reactions by the release of their granule-derived cytotoxic proteins. However, an increasing number of experimental observations indicate that eosinophils also are multifunctional leukocytes involved in diverse inflammatory and physiologic immune responses. Under homeostatic conditions, eosinophils are particularly abundant in the lamina propria of the gastrointestinal tract, where their involvement in various biological processes within the gastrointestinal tract has been posited. In this review, we summarize the molecular steps involved in eosinophil development and describe eosinophil trafficking to the gastrointestinal tract. We synthesize the current findings on the phenotypic and functional properties of gastrointestinal eosinophils and the accumulating evidence that they have a contributory role in gastrointestinal disorders, with a focus on primary eosinophilic gastrointestinal disorders. Finally, we discuss the potential role of eosinophils as modulators of the intestinal immune system.

Figure 1. Phenotypic and functional properties of gastrointestinal eosinophils

(A) In healthy conditions, eosinophils develop in the bone marrow and migrate to the lamina propria of gastrointestinal tract by a process regulated by CCR3/eotaxin-1. IL-5 secreted by ILC2 and cytokine signaling through the γc-chain receptors increases the life-span of small-intestinal eosinophils. Coexpression of IL-5 and IL-13 by ILC2 is enhanced by nutrient uptake, VIP stimulation, and IL-33. Eosinophil SIRP-α inhibits degranulation by interaction with membranous protein CD47, thus promoting eosinophil survival. IL-5 and eotaxin signaling is regulated by the opposing actions of PIR-A and PIR-B.(B) Eosinophils express a broad range of pattern-recognition (PRR) and Fc gamma receptors (FcγR), allowing them to be stimulated by various pathogens including bacteria, virus, and antibody-coated pathogens including helminths. Cytoplasmic granules and eosinophilic mitochrondrial DNA secreted by gastrointestinal eosinophils mediate tissue pathology and particulate in host clearance of pathogens. Eosinophils stimulated by Th2 type cytokines and epithelium-derived IL-33 mediate tissue inflammation in a variety of primary eosinophilic gastrointestinal disorder. Eosinophils may also modulate T cell–mediated immune responses, IgA class switching, and glucose homeostasis.