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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 program of eosinophils arising in IL5-depleted or IL5-replete human or murine hosts, at steady-state in vivo and following in vitro stimulation 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.

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We thank S. Couillard for his interesting comments related to our publication on the effects of interleukin (IL)-5 deficiency on the transcriptome of residual eosinophils of Il5-deficient mice and mepolizumab-treated patients [1]. We indeed document stronger upregulation of the expression of the SOCS3 gene following stimulation with IL-33 ex vivo that is conserved between eosinophils from mepolizumab-treated patients and from Il5-deficient mice.We do not question that this specific response of IL-5-deprived eosinophils might have biological implications since SOCS3 is an important gene in asthma. Indeed, SEKI et al. [2] reported that SOCS3 gene expression in peripheral T cells correlates with asthma severity and that transgenic mice in which the Socs3 gene is overexpressed specifically in T cells develop more robust T-helper type 2 (Th2) responses and associated airway allergy. Further, genetic association studies pinpointed the SOCS3 locus as a suspected driver of asthma risk [3]. We discussed these findings.Nonetheless, we advise caution in interpreting and extrapolating our specific observation in eosinophils for several reasons. From a purely technical standpoint first, our study of the response to IL-33 was performed ex vivo on isolated eosinophils, as a way of modelling eosinophil activation. It remains to be determined whether a similar difference in SOCS3 gene induction in eosinophils would be observed in the airways of mepolizumab-treated asthma patients or Il5-deficient mice, in which the immune microenvironment is obviously more complex. In addition, caution is warranted when extrapolating gene expression data, as changes in gene expression are not always reflected at the protein, and hence functional level. It remains unknown whether SOCS3 protein levels would be sufficiently affected in eosinophils of IL-5-depleted hosts to the point of altering eosinophil behaviour.Second, from a conceptual standpoint, S. Couillard proposes an interesting but speculative extrapolation. He proposes that increased SOCS3 gene responsiveness to IL-33 in IL-5-deprived eosinophils could make them more prone to recruitment or activation and contribute to asthma exacerbations in a subset of asthma patients treated with anti-IL-5 biologicals, as reported in the MEX study [4]. It has however to be noted that SOCS3 is mostly suspected to affect asthma risk through the T cell intrinsic impact it has on T cell polarisation into Th2 cells [2, 5], which are major drivers of the atopic T2 asthma endotype [6]. The role of SOCS3 in eosinophils themselves remains in comparison poorly studied and there has been no experimental evidence so far that SOCS3-overexpressing eosinophils would be more prone to activation, or "trigger happy" as S. Couillard puts it. It is yet a hypothesis worth testing, as we discussed.We actually believe that two non-mutually exclusive models of eosinophil biology should be considered to better understand clinical observations such as those of the MEX study. A first model, in line with S. Couillard's hypothes...