Abstract
An important immunopathological hallmark of allergic disease is tissue eosinophilic and basophilic inflammation, a phenomenon which originates from hemopoietic progenitors (HP). The fate of HP is determined by local inflammatory cytokines that permit “in situ hemopoiesis,” which leads to the accumulation of eosinophils and basophils (Eo/B). Given that recent evidence supports a critical immunomodulatory role for thymic stromal lymphopoietin (TSLP) in allergic inflammation, as well as TSLP effects on CD34+ progenitor cytokine and chemokine secretion, we investigated the role of TSLP in mediating eosinophilo- and basophilopoiesis, the mechanisms involved, and the association of these processes with atopic sensitisation. In the studies presented herein, we demonstrate a direct role for TSLP in Eo/B differentiation from human peripheral blood CD34+ cells. In the presence of IL-3, TSLP significantly promoted the formation of Eo/B colony forming units (CFU) (including both eosinophils and basophils) from human HP (HHP), which was dependent on TSLP–TSLPR interactions. IL-3/TSLP-stimulated HHP actively secreted an array of cytokines/chemokines, key among which was TNFα, which, together with IL-3, enhanced surface expression of TSLPR. Moreover, pre-stimulation of HHP with IL-3/TNFα further promoted TSLP-dependent Eo/B CFU formation. HHP isolated from atopic individuals were functionally and phenotypically more responsive to TSLP than those from nonatopic individuals. This is the first study to demonstrate enhanced TSLP-mediated hemopoiesis ex vivo in relation to clinical atopic status. The capacity of HHP to participate in TSLP-driven allergic inflammation points to the potential importance of “in situ hemopoiesis” in allergic inflammation initiated at the epithelial surface.
Highlights
The airway epithelium is an important initiator of the allergic response; it secretes cytokines/chemokines, which regulate innate immune cells [1]
The addition of thymic stromal lymphopoietin (TSLP) significantly increased the formation of IL-3-responsive eosinophils and basophils (Eo/B) colony forming units (CFU) from 7.56 Æ 0.9 to 15.8 Æ 1.6 (P < 0.001; Fig. 1a), which was inhibited by the addition of neutralizing anti-TSLP (9.3 Æ 1.0 per 8000 CD34þ cells; P < 0.05) and anti-TSLPR (10.6 Æ 1.1 per 8000 CD34þ cells; P < 0.05)
We demonstrate for the first time that peripheral blood (PB) human HP (HHP) respond directly to TSLP in vitro with enhanced Eo/B colony formation and TSLPR/IL-7Ra expression, upon co-stimulation with IL-3, and not IL-5 or GM-CSF
Summary
The airway epithelium is an important initiator of the allergic response; it secretes cytokines/chemokines, which regulate innate immune cells [1]. One such cytokine is thymic stromal lymphopoietin (TSLP), an IL-7-like cytokine [2], which can be elicited from human airway epithelial cells by cytokines and pathogen-associated molecular patterns [3, 4]. TSLP is known to signal through the JAK/STAT and MAPK pathways [10, 11], both of which are involved in the differentiation of hemopoietic progenitor cells into eosinophils [12, 13]. Human eosinophils and basophils are closely linked during development and share a common progenitor [14,15,16], while in the mouse these differentiative pathways appear distinct [17]
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