Reply: Ex vivo SOCS3 gene responsiveness to alarmins in eosinophils of mepolizumab-treated patients is as yet of unknown biological significance

Abstract

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...