IL-33 Precedes IL-5 in Regulating Eosinophil Commitment and Is Required for Eosinophil Homeostasis

Abstract

Eosinophils are important in the pathogenesis of many diseases, including asthma, eosinophilic esophagitis, and eczema. While IL-5 is crucial for supporting mature eosinophils, the signals that support earlier eosinophil lineage events are less defined. The IL-33 receptor, ST2, is expressed on several inflammatory cells, including eosinophils, and is best characterized for its role during the initiation of allergic responses in peripheral tissues. Recently, ST2 expression was described on hematopoietic progenitor subsets, where its function remains controversial. Our findings demonstrate that IL-33 is required for basal eosinophil homeostasis, since both IL-33– and ST2-deficient mice exhibited diminished peripheral blood eosinophil numbers at baseline. Exogenous IL-33 administration increased mature eosinophils in both the bone marrow and periphery in WT and IL-33–deficient, but not ST2-deficient, mice. Systemic IL-5 was also increased under this treatment, and blocking IL-5 with a neutralizing antibody ablated of the IL-33-induced mature eosinophil expansion. The homeostatic hypereosinophilia seen in IL-5–transgenic mice was significantly lower with ST2 deficiency despite similar elevations in systemic IL-5. Finally, in vitro treatment of bone marrow cells with IL-33, but not IL-5, led to specific early expansion of IL-5Rα–expressing precursor cells. In summary, our findings establish a basal defect in eosinophilopoiesis in IL-33– and ST2-deficient mice and a mechanism whereby IL-33 supports mature eosinophils by driving both systemic IL-5 production and the expansion of IL-5Rα–expressing precursor cells.

Type 2 Cytokine Responses: Regulating Immunity to Helminth Parasites and Allergic Inflammation

“…Further, it is well established that the IL-33 receptor (ST2) is expressed on a variety of type 2 cytokine-related HSPCs including eosinophil, basophil and mast cell progenitors suggesting IL-33 may also be capable of promoting progenitor cell responses. This is supported by recent work demonstrating that IL-33 plays a critical role in regulating murine eosinophil hematopoiesis (162). Supporting these murine studies, elevated CD34 + progenitor cell populations have been identified in the inflamed tissues of patients suffering from nasal polyposis and asthma (162, 163).…”

“…This is supported by recent work demonstrating that IL-33 plays a critical role in regulating murine eosinophil hematopoiesis (162). Supporting these murine studies, elevated CD34 + progenitor cell populations have been identified in the inflamed tissues of patients suffering from nasal polyposis and asthma (162, 163). Collectively, these studies suggest that cytokine alarmins not only recruit HSPCs to peripheral tissues but also alter their functional properties, enabling them to selectively promote type 2 responses (Fig.…”

Understanding Interleukin 33 and Its Roles in Eosinophil Development

“…Importantly, although EoP stains with eosin, eosin-negative precursors have been reported (42), suggesting a precursor stage prior to the granulation events occurring in EoP. We identified an EoPre that is eosin negative and exhibits the characteristic donut-shaped nuclei, which is driven by IL-33 exposure (44) (Figure 1A). Both EoP and EoPre are IL-5Rα + , but EoPre is Siglec-F lo SSC lo whereas EoP is Siglec-F + SSC hi .…”

Proteomic and Phosphoproteomic Changes Induced by Prolonged Activation of Human Eosinophils with IL-3

“…IL1RAP is co-receptor with IL1R1 for IL1 and with IL1RL1 for IL-33 signaling. The receptor for IL-33, IL1RL1/IL1RAP is expressed on mature blood and airway EOS, and EOS progenitors (29–31) . IL-33 activates EOS to release cytokines such as GM-CSF, which increases their survival in an autocrine manner (32, 33) .…”