Abstract
Understanding the signals that regulate eosinophil survival and death is critical to developing new treatments for asthma, atopy, and gastrointestinal disease. Previous studies suggest that TNF-α stimulation protects eosinophils from apoptosis, and this TNF-α-mediated protection is mediated by the upregulation of an unknown protein by NF-κB. Here, we show for the first time that eosinophils express the caspase 8-inhibitory protein c-FLIP, and c-FLIP expression is upregulated upon TNF-α stimulation. Considering that c-FLIP expression is regulated by NF-κB, we hypothesized that c-FLIP might serve as the “molecular switch” that converts TNFRI activation to a pro-survival signal in eosinophils. Indeed, we found that one c-FLIP isoform, c-FLIPL, is required for mouse eosinophil survival in the presence of TNF-α both in vitro and in vivo. Importantly, our results suggest c-FLIP as a potential therapeutic target for the treatment of eosinophil-mediated disease.
Highlights
Eosinophils were one of the first types of leukocytes to be described, their physiologic and pathologic functions remain poorly understood
Because NF-kB activation upregulates the expression of the anti-apoptotic protein cFLIP in many cell types [8,9,10,11], we hypothesized that TNF-a stimulation may upregulate c-FLIP in eosinophils
Due to the paucity of circulating eosinophils in vivo, we examined the mRNA expression of c-FLIP in bone marrowderived eosinophils (BMDEs) from wild type mice by qPCR (Fig. 1A, B)
Summary
Eosinophils were one of the first types of leukocytes to be described, their physiologic and pathologic functions remain poorly understood. After development from hematopoietic progenitors, mature eosinophils circulate for less than a day before homing to the gastrointestinal tract, thymus, mammary glands, or uterus, where they are thought to function in antigen presentation, T cell polarization, thymocyte selection, mammary gland development, and reproduction [1]. Accumulating evidence points to a role for eosinophils in the clearance of bacterial and viral pathogens; these functions can result in pathology in the lung [4]. In addition to these proposed functions in promoting immunity and maintaining homeostasis, eosinophils have been implicated in numerous pathological states, including allergy, asthma, and gastrointestinal disease. The mechanisms by which eosinophils mediate these diseases remain unclear; developing strategies to deplete or inhibit eosinophils is a subject of intense research
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