Wiskott–Aldrich Syndrome Protein Is Required for Glucocorticoid‐Dependent Eosinopoiesis and Eosinophil‐Rich Inflammation in Murine Models

Wiskott-Aldrich Syndrome Protein (WASP) is a pleiotropic cytoskeletal regulator expressed in haematopoietic tissues that plays essential roles in immune cell function, including leukocyte migration and signalling. By contrast, WASP's roles in leukocyte production remain insufficiently explored. Recent observations of the regulation of murine eosinophil production by distinct signalling pathways, respectively involving glucocorticoids (GCs) and cysteinyl leukotrienes (CysLTs), prompted us to investigate their dependence on WASP. To explore the contribution of WASP to eosinophil development and its relationship to GC- and CysLT-dependent regulatory pathways in vivo and ex vivo. We used wild-type (WT) and WASP-deficient mice in models of thioglycolate-induced peritonitis, allergic asthma and surgical stress to assess eosinophil recruitment and production. We used ex vivo cultures, co-culture systems and pharmacological interventions (dexamethasone, hydrocortisone, indomethacin, leukotriene receptor agonist and antagonist) to evaluate eosinophil differentiation and regulation of the eosinopoietic microenvironment. WASP-deficient mice displayed reduced eosinophil accumulation at extramedullary inflammatory sites and failed to mount a GC-induced eosinopoietic response. This defect was associated with the adherent stromal-enriched compartment, as GC responsiveness was restored when WASP-deficient progenitors were co-cultured with WT adherent bone marrow cells. Conversely, CysLT-driven eosinopoiesis remained intact in WASP-deficient mice. Our findings indicate that GC-mediated induction of eosinopoiesis depends on a WASP-sensitive, heterogeneous adherent bone marrow compartment. In contrast, the CysLT pathway remains functional in the absence of WASP. These results suggest that WASP contributes to eosinophil production through effects associated with the adherent haematopoietic microenvironment, while the precise cellular subset responsible remains to be defined.