Asthma is now recognized as a heterogeneous disease, encompassing different phenotypes driven by distinct pathophysiological mechanisms called endotypes. Common phenotypes of asthma, referred to as eosinophilic asthma, are characterized by the presence of eosinophilia. Eosinophils are usually considered invariant, terminally differentiated effector cells and have become a primary therapeutic target in severe eosinophilic asthma (SEA) and other eosinophil-associated diseases (EADs). Biological treatments that target eosinophils reveal an unexpectedly complex role of eosinophils in asthma, including in SEA, suggesting that “not all eosinophils are equal”. In this review, we address our current understanding of the role of eosinophils in asthma with regard to asthma phenotypes and endotypes. We further address the possibility that different SEA phenotypes may involve differences in eosinophil biology. We discuss how these differences could arise through eosinophil “endotyping”, viz. adaptations of eosinophil function imprinted during their development, or through tissue-induced plasticity, viz. local adaptations of eosinophil function through interaction with their lung tissue niches. In doing so, we also discuss opportunities, technical challenges, and open questions that, if addressed, might provide considerable benefits in guiding the choice of the most efficient precision therapies of SEA and, by extension, other EADs.

Neutralising antibodies against the cytokine interleukin (IL)5 have become widely used for the control of severe eosinophilic asthma. Remarkably, patients receiving neutralising anti-IL5 biological therapies retain a very stable population of residual blood eosinophils. Whether these residual eosinophils are endowed with particular biological activity has not yet been studied, but is of importance in predicting potential long-term effects of IL5 neutralisation in patients. To tackle the effect of IL5 depletion on residual eosinophils, we used a comparative RNA-sequencing approach and compared the gene expression programme of eosinophils arising in IL5-depleted or IL5-replete human or murine hosts, at steady-statein vivoand followingin vitrostimulation with the eosinophil-activating alarmin IL33. We compared blood eosinophils from patients with severe allergic eosinophilic asthma treated with anti-IL5 mepolizumab therapy to those of healthy controls and matched asthma patients receiving anti-IgE omalizumab therapy. We made similar comparisons on bone marrow eosinophils from mice genetically deficient or not for IL5. We report that restriction of IL5 availability did not elicit any detectable transcriptional response in steady-state residual eosinophils in mepolizumab-treated patients or IL5-deficient mice, and influenced only a handful of genes in their response to IL33. Together, these results support the notion that treatment with IL5 neutralising antibodies spares a pool of circulating residual eosinophils largely resembling those of healthy individuals.

Interleukin-5 (IL)-5 is an essential driver of eosinophilia which correlates with disease severity in severe eosinophilic asthma (SEA). Treatment with anti-IL5 biological therapies alleviates eosinophilia and provides clinical benefits in the control of SEA. Curiously, a stable and interindividually consistent population of residual eosinophils persists in the blood following anti-IL5 mepolizumab treatment. Whether these residual eosinophils possess particular biological activity is unknown but of clinical relevance in predicting long-term effects of IL5 neutralization. In this study, we aimed at identifying potential biological alterations of residual blood eosinophils following IL5 deprivation. Therefore, we compared the gene expression program of eosinophils in IL5-depleted or IL5-replete human and murine hosts, at steady state in vivo and following stimulation by eosinophil-activating alarmin IL33 ex vivo. First, by comparing bone marrow eosinophils of mice genetically deficient or not for IL5. Second, by comparing eosinophils in the blood of patients with SEA treated with mepolizumab compared to healthy controls and matched patients receiving omalizumab treatment. Restriction of IL5 availability did not elicit any demonstrable transcriptional response in residual eosinophils from mepolizumab treated patients or IL5-deficient mice, and only affected a handful of genes in their response to IL33. From a clinical perspective, these results suggest that long-term IL5 biological therapy spares a pool of residual eosinophils that resemble those of healthy controls. Fundamentally, we suggest that IL5 does not impact on eosinophil development but rather their expansion.