Thymic stromal lymphopoietin: master switch for allergic inflammation

Abstract

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL) 7-like cytokine that triggers dendritic cell-mediated T helper (Th)2 inflammatory responses. TSLP is highly expressed by keratinocytes in skin lesions of patients with atopic dermatitis and is associated with dendritic cell activation in situ, suggesting that TSLP might be a master switch for allergic inflammation at the epithelial cell-dendritic cell interface. New reports now establish a direct link between TSLP expression and the pathogenesis of atopic dermatitis and asthma in vivo, and begin to reveal the molecular mechanisms underlying TSLP-induced allergic inflammation.

Figure 1.

TSLP expression in atopic dermatitis associates with Langerhan's cell migration and activation. Normal skin contains Langerin⁺ langerhan's cells (blue) in the epidermis (a and c) and DC-lamp⁺ DCs (blue) in the epidermis and dermis (b and d). TSLP (red) is not expressed in normal skin (a and b). However, skin lesions from patients with atopic dermatitis express high levels of TSLP (c), which is associated with the migration of Langerhan's cells from the epidermis to the dermis (d). Reprinted with permission from Nature Immunology (Soumelis V., P.A. Reche, H. Kanzler, W. Yuan, G. Edward, B. Homey, M. Gilliet, S. Ho, S. Antonenko, A. Lauerma, et al. 2002. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat. Immunol. 3:673–680.).

Figure 2.

Pathophysiology of TSLP in allergic inflammation. Insults from allergens or viruses trigger mucosal epithelial cells or skin cells (keratinocytes, fibroblasts, and mast cells) to produce TSLP (step 1). TSLP activates immature DCs (step 2). TSLP-activated DCs produce the chemokines IL-8 and eotaxin-2, which attract neutrophils and eosinophils, as well as TARC and MDC, which attract Th2 cells (step 3). TSLP-activated mDCs mature and migrate into the draining lymph nodes (step 4). TSLP-activated DCs also express OX40L, which triggers the differentiation of allergen-specific naive CD4⁺ T cells to inflammatory Th2 cells that produce IL-4, IL-5, IL-13, and TNF but not IL-10 (step 5). Inflammatory Th2 cells then migrate back to the site of inflammation because of the local production of TARC and MDC (step 6). The Th2 cytokines IL-4, IL-5, IL-13, and TNF, produced by the inflammatory Th2 cells, initiate allergic inflammation by triggering IgE production, eosinophilia, and mucus production (step 7).