Summary Allergy describes a constellation of clinical diseases that affect up to 30% of the world’s population. It is characterized by production of allergen specific IgE which bind to mast cells and initiate a cascade of molecular and cellular events that affect the respiratory tract (rhinitis and asthma) skin (dermatitis, urticaria) and multi systems (anaphylaxis) to a variety of allergens including pollens, mold spores, animal danders, insect stings, foods and drugs. The underlying pathophysiology involves immunoregulatory dysfunctions similar to those noted in highly stressed populations. The relationships in terms of potentials for intervention are discussed.

Both the IL-4/IL-13 and TSLP pathways have been proposed to drive type 2 inflammation in preclinical models of allergic disease. However, to date, only blockade of the IL-4/IL-13 pathway has demonstrated clinical efficacy in the treatment of multiple diseases with underlying type 2 signatures, including atopic dermatitis (AD), asthma and chronic sinusitis with nasal polyposis. Here, we perform a thorough mechanistic comparison of the IL-4/IL-13 and TSLP pathways in promoting type 2 inflammation. METHODS: Wildtype (WT) and IL-4Ra knockout (KO) mice were subjected to systemic TSLP overexpression via hydrodynamic DNA (HDD) injection. A week later, serum, lung and lymphoid organs were characterized for type 2 inflammation-associated endpoints. RESULTS: TSLP-driven effects on hallmark features of type 2 immunity (goblet cell metaplasia, serum IgE and lung tissue eosinophilia) are abrogated in the context of IL-4Ra deficiency. In addition, TSLP overexpression also dramatically changed the landscape of mononuclear phagocytes (MPs) in the lung. For example, the frequency of alveolar macrophages, the major myeloid population of the lung which serves to maintain lung homeostasis, is significantly diminished by TSLP overexpression in WT mice, but remains unaffected in IL-4Ra KO mice. CONCLUSIONS: Here, we demonstrate that TSLP-driven effects on type 2 inflammation are predominantly through the IL-4Ra-dependent pathway. TSLP promoted lung tissue eosinophilia and depletion of alveolar macrophages, which are unequivocal measures of poor lung health. These endpoints were absent in the IL-4Ra KO mice, suggesting that IL-4Ra deficiency is sufficient to maintain lung health in the context of type 2 inflammation.