Blockade of thymic stromal lymphopoietin and CRTH2 attenuates airway inflammation in a murine model of allergic asthma

Background/Aims: Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that plays a key role in Th2-mediated inflammation, both directly by promoting the proliferation of naïve CD₄ Th₂ cells, and indirectly by activating dendritic cells (DCs). TSLP-activated DCs induce the expansion of che-moattractant receptor homologous molecule expressed on Th₂ (CRTh₂)⁺ CD4⁺ Th₂ memory cells, which undergo a Th₂ response and express prostaglandin D₂ (PGD₂) synthase. CRTh₂, a PGD₂ receptor, is a selective Th₂-cell surface marker. We investigated the effects of an anti-TSLP antibody (Ab) and a CRTh₂ antago-nist, as well as their mechanisms of action, in a mouse model of acute asthma. Methods: BALB/c mice were sensitized and challenged with ovalbumin. We then evaluated the effects of the administration of an anti-TSLP Ab either alone or together with a CRTh₂ antagonist on cell counts, Th₂ cytokine levels in bron-choalveolar fluid, and the levels of epithelium-derived cytokines such as TSLP, interleukin (IL) 33, and IL-25 in lung homogenates, as well as airway hyper-re-sponsiveness (AHR). Results: Anti-TSLP Ab and the CRTh₂ antagonist significantly attenuated eosin-ophilic airway inflammation, AHR, and the expression of Th₂ cytokines. The expression of GATA-3 and the levels of IL-33 and IL-25 in lung tissues were affected by the combined anti-TSLP and CRTh₂ antagonist treatment. Conclusions: These results suggest that the dual blockade of TSLP and CRTh₂ may serve as an effective treatment target for eosinophilic asthma.