Figure 2: Simplified model of the HDM-induced innate immune activation leading to allergic asthma. The induction of Th2 immunity by HDM allergens results from the stimulations of different innate immune pathways. HDM protease allergens specifically cleave protease-sensitive receptors including PAR-2, disrupt epithelial barrier to gain access to DCs, and cause tissue injuries to release DAMPs such as ATP and uric acid. Contaminating microbial PAMPs associated or not with lipid-binding allergens trigger numerous PRRs which can produce also DAMPs whereas HDM glycan activation of DCs is mediated through CLR ligation. These signaling pathways result in the massive upregulation of innate cytokines/chemokines as IL-1β, IL-6, TSLP, IL-25, IL-33, GM-CSF, or CCL20 to recruit and activate inflammatory cells and to induce Th2 differentiation. Notably, TSLP mediates OX40L and IL-4 expression in DCs and basophils, respectively, to initiate Th2-polarized response. IL-25 as well as IL-33 are strong activators of ILC2s which, similar to allergen-specific Th2 cells, provide large amount of the Th2 cytokines IL-5 and IL-13 to generate the main features of the allergic airway inflammation such as IgE secretion by B cells, eosinophil recruitment, and airway remodeling.