Heterogeneity of Intestinal Tissue Eosinophils: Potential Considerations for Next-Generation Eosinophil-Targeting Strategies

Abstract

Eosinophils are implicated in the pathophysiology of a spectrum of eosinophil-associated diseases, including gastrointestinal eosinophilic diseases (EGIDs). Biologics that target the IL-5 pathway and are intended to ablate eosinophils have proved beneficial in severe eosinophilic asthma and may offer promise in treating some endotypes of EGIDs. However, destructive effector functions of eosinophils are only one side of the coin; eosinophils also play important roles in immune and tissue homeostasis. A growing body of data suggest tissue eosinophils represent a plastic and heterogeneous population of functional sub-phenotypes, shaped by environmental (systemic and local) pressures, which may differentially impact disease outcomes. This may be particularly relevant to the GI tract, wherein the highest density of eosinophils reside in the steady state, resident immune cells are exposed to an especially broad range of external and internal environmental pressures, and greater eosinophil longevity may uniquely enrich for co-expression of eosinophil sub-phenotypes. Here we review the growing evidence for functional sub-phenotypes of intestinal tissue eosinophils, with emphasis on the multifactorial pressures that shape and diversify eosinophil identity and potential targets to inform next-generation eosinophil-targeting strategies designed to restrain inflammatory eosinophil functions while sustaining homeostatic roles.

Single-cell RNA sequencing unveils intestinal eosinophil development and specialization

“…Our findings suggests that eosinophil subpopulations emerge from consecutive maturation steps and adaptation to distinct niches. This observation corroborates proposals that the considerable morphological and phenotypic variability of tissue eosinophils reflects their adaptation to different microenvironments (Abdala-Valencia et al, 2018;Masterson et al, 2021). In the GI tract, active, but not basal eosinophils exhibited strong transcriptional and phenotypical heterogeneity across compartments, suggesting this subset readily adapts to local microbial, tissue and cytokine cues.…”

“…Eosinophils exhibit considerable phenotypical, morphological and functional diversity within tissues (Mesnil et al, 2016;Xenakis et al, 2018), indicating the existence of specialized subset with tissue-protective or pro-inflammatory functions (Abdala-Valencia et al, 2018;Masterson et al, 2021). Thus, delineation of eosinophil subpopulations is required to develop refined targeting strategies harnessing eosinophil pathological activities.…”

The aryl hydrocarbon receptor contributes to tissue adaptation of intestinal eosinophils in mice

“…Here, we show that eosinophils profoundly change their transcriptome from the bone marrow to the small intestine, highlighting for the first time that eosinophils undergo tissue adaptation. Although some level of heterogeneity between eosinophils from different tissues has long been recognized, particularly in their expression of surface markers ( Masterson et al, 2021 ), the concept of tissue adaptation as such has not been explored for eosinophils. More recent publications have described subsets of eosinophils within the intestine and lung ( Mesnil et al, 2016 ; Xenakis et al, 2018 ), but eosinophils were not directly compared between different tissues.…”

“…It is possible that increased activation of NF-κB and the MAPK pathway in the absence of AHR may prolong the survival of eosinophils ( Kankaanranta et al, 1999 ; Schwartz et al, 2015 ). We did not fully explore how AHR interacts with the range of signals and pathways that have been shown to regulate eosinophil survival ( Masterson et al, 2021 ; Park and Bochner, 2010 ; Shen and Malter, 2015 ) and cannot rule out that additional mechanisms are involved. For example, ST18 was the most upregulated transcription factor in WT versus Ahr –/– eosinophils.…”

Eosinophils, beyond IL-5

“…Although eosinophils have some negative effects on numerous gastrointestinal diseases, in their review, Masterson et al [19] stress the danger of depleting populations of eosinophils with beneficial anti-inflammatory and homeostatic functions, particularly in the intestine. They provide a remarkable detailed description of the eosinophil varieties (endotypes) regarding responses to in vivo environments and their numerous functions in tissues.…”