Thymic Stromal Lymphopoietin Induces Chemotactic and Prosurvival Effects in Eosinophils

Abstract

Thymic stromal lymphopoietin (TSLP) is highly expressed by bronchial epithelial cells and skin keratinocytes in allergic diseases. TSLP acts as a master switch for allergic inflammation through the activation of dendritic cells and mast cells for initiating inflammatory type 2 T-helper lymphocyte responses. To elucidate the immunological cascades of epithelium/keratinocyte-eosinophil-mediated allergic inflammation, we examined the modulating effects of TSLP on human eosinophils. Expression of TSLP receptor complex was detected by RT-PCR, flow cytometry, and Western blot. Adhesion molecules, cytokine, and chemokines were quantitated by flow cytometry or ELISA. Intracellular signal transduction molecules were measured by Western blot and flow cytometry. We observed that human eosinophils constitutively expressed functional heterodimeric TSLP receptor complex comprising TSLP-binding chain TSLPR and IL-7Ralpha chain. TSLP could significantly delay eosinophil apoptosis, up-regulate cell surface expression of adhesion molecule CD18 and intercellular adhesion molecule-1, but down-regulate L-selectin, enhance eosinophil adhesion onto fibronectin, and induce the release of inflammatory cytokine IL-6 and chemokines CXCL8, CXCL1, and CCL2 (all P < 0.05). All these effects were concentration dependent and TSLP specific. TSLP regulated the above effects through the activation of extracellular signal-regulated protein kinase, p38 mitogen-activated protein kinase, and NF-kappaB signaling pathway, but not signal transducer and activator of transcription 5 and 3, which were usually activated in other effector cells upon TSLP stimulation. Collectively, the above findings elucidate the proallergic mechanisms of TSLP via the activation of distinct intracellular signaling pathways in eosinophils.

Clinical Characteristics and Expression of Thymic Stromal Lymphopoetin in Eosinophilic and Non-Eosinophilic Chronic Rhinosinusitis

“…Similarly, Wong et al [26] have demonstrated that TSLPR was expressed in eosinophils isolated and cultured from the blood of healthy volunteers. Consistent with these findings, our study demonstrated that TSLP was expressed in epithelial cells, plasma cells and inflammatory cells in the nasal mucosa of patients in both the ECRS and NECRS groups.…”

The Chemokine System in Innate Immunity

“…This leads to the inhibition of CCR3-mediated chemotaxis, and ultimately to the suppression of eosinophilic inflammation (Struyf et al 1999;Yan et al 2012). Finally, analogous to the inflammation-amplification mechanisms used by other acute inflammatory cells, thymic stromal lymphopoietin (TSLP) -stimulated eosinophils also produce CCL2, CXCL1, and CXCL8 promoting further influx of inflammatory monocytes and neutrophils (Wong et al 2010).…”

Thymic Stromal Lymphopoietin Contributes to Myeloid Hyperplasia and Increased Immunoglobulins, But Not Epidermal Hyperplasia, in RabGEF1-Deficient Mice

“…9 Recently, TSLP has been shown to promote survival, cytokine and chemokine release, and up-regula-tion of adhesion molecules in human eosinophils. 10 These observations suggest that TSLP can orchestrate allergic inflammation by activating cells of both the adaptive and the innate immune systems. In accord with this notion, transgenic mice expressing TSLP under the regulation of the keratinocyte-specific promoters for keratin-14 11 or keratin-5 12 develop atopic dermatitis-like skin lesions, with inflammatory infiltrates including eosinophils and lymphocytes, and also exhibit pronounced splenomegaly, lymphadenopathy, and elevated serum levels of IgE and IgG1 antibodies.…”