Short and dysfunctional telomeres protect from allergen‐induced airway inflammation. Issue 5 (4th May 2021)

• Record Type: Journal Article
• Authors: Piñeiro‐Hermida, Sergio; Martínez, Paula; Blasco, Maria A.
• Is Part Of: Aging cell. Volume 20:Issue 5(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-05-04
• Subjects: 6‐thio‐dG -- allergy -- house dust mite (HDM) -- telomerase -- telomeres; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.13352
• Languages: English
• ISSNs: 1474-9718

Abstract

Abstract: Asthma is a chronic inflammatory disease affecting 300 million people worldwide. As telomere shortening is a well‐established hallmark of aging and that asthma incidence decreases with age, here we aimed to study the role of short telomeres in asthma pathobiology. To this end, wild‐type and telomerase‐deficient mice with short telomeres (third‐generation (G3 Tert −/− mice)) were challenged with intranasal house dust mite (HDM) extract. We also challenged with HDM wild‐type mice in which we induced a telomere dysfunction by the administration of 6‐thio‐2´‐deoxyguanosine (6‐thio‐dG). Following HDM exposure, G3 Tert −/− and 6‐thio‐dG treated mice exhibited attenuated eosinophil counts and presence of hematopoietic stem cells in the bone marrow, as well as lower levels of IgE and circulating eosinophils. Accordingly, both G3 Tert −/− and 6‐thio‐dG treated wild‐type mice displayed reduced airway hyperresponsiveness (AHR), as indicated by decreased airway remodeling and allergic airway inflammation markers in the lung. Furthermore, G3 Tert −/− and 6‐thio‐dG treated mice showed lower differentiation of Club cells, attenuating goblet cell hyperplasia. Club cells of G3 Tert −/− and 6‐thio‐dG treated mice displayed increased DNA damage and senescence and reduced proliferation. Thus, short/dysfunctional telomeres play a protective role in murine asthma by impeding both AHR and mucus secretion after HDM exposure. Therefore, our findings imply that telomeres play a relevant role in allergen‐induced airway inflammation. Abstract : Diminished expression of SOX2 in airway epithelial Club cells of mice with short and dysfunctional telomeres prevents differentiation of Club cells to goblet cells, reducing mucus secretion and eosinophil recruitment to the lung upon house dust mite (HDM)‐induced allergy. Club cells of mice with short/dysfunctional telomeres also displayed increased DNA damage (γ‐H2AX) and senescence (p21), as well as decreased proliferation (Ki67). Moreover, decreased bone marrow myelopoiesis (CD34) in these mouse models also contributes to reduced presence of eosinophils in the lung.