Uncover the role of skin- and lung-derived cytokine “thymic stromal lymphopoietin” in the onset of asthma – EPIMONA

Asthma is a chronic inflammatory disease of airways characterized by recurrent episodes of airway obstruction and wheezing. Its prevalence is steadily increasing worldwide, affecting approximately 10% of children and 3% of adults. A long term effective treatment of asthma is still missing, probably because most of the current treatments, including steroid therapies and beta2-adrenoceptor agonists, are aimed at controlling the inflammation or relieving airway symptoms, rather than at targeting events involved in the initiation of the disease.
A phenomenon known as the “atopic march” has been long observed, as the development of asthma is often preceded by clinical signs of atopic dermatitis (AD, eczema), characterized by pruritic, eczematoid skin lesions, frequently starting in early infancy and peaking in the first year of life. Strikingly, more than 50% of AD patients with moderate to severe AD, develop asthma and/or allergic rhinitis later in life. In addition, the severity of AD seems to influence the course of respiratory allergy. How asthma is initiated and progresses, particularly what could be the mechanisms linking AD and asthma, remains still unclear.
The major goal of our study is to uncover the cellular and molecular mechanisms underlying asthma pathogenesis by using mouse models. One of the most commonly used experimental asthma protocols is based on intraperitoneal (i.p.) sensitization with ovalbumin (OVA) precipitated in aluminium hydroxide (as exogenous adjuvant), followed by repeated OVA airway challenge. Although a phenotype recapitulating the characteristic features of human asthma was generated, this mouse model does not mimic the allergen sensitization in real life, and is not suitable to study how asthma is initiated and progresses. To better mimic the onset of human asthma, we will establish new mouse experimental asthma protocols using specific allergen [OVA or house dust mite (HDM, the most relevant aeroallergen involved in human asthma)], in which asthmatic phenotypes will be generated by allergen sensitization occurring through skin or airway epithelium (the two main sites of initiation of sensitization), followed by allergen challenge in airways. We will then employ these protocols to investigate, in the onset of asthma, the role of one epithelium-derived cytokine thymic stromal lymphopoietin (TSLP), whose expression was found to be increased in skin epidermis of human AD patients, as well as in airways from asthma patients. By combining mouse genetic approaches and cellular and molecular tools, we intend to: 1) study the role of TSLP locally produced in the skin or the lung in priming allergen sensitization, as well as in generating asthmatic inflammation upon allergen challenge; 2) investigate whether and how TSLP produced from AD skin may trigger the sensitization to allergen through epithelia, thus playing a key role in the atopic march; 3) elucidate the cellular and molecular mechanisms underlying the role of TSLP in the onset of asthma. These studies are expected to give us a better knowledge of the mechanisms of asthma pathogenesis, which may lead to the prevention of atopic march and more effective treatment of asthma.