- Title
- Understanding how group 2 innate lymphoid cells in early life regulate postnatal lung development and susceptibility to chronic lung diseases
- Creator
- Loering, Svenja
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2022
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Mammalian lung development begins in utero and continues after birth. In mice, the first two weeks of life are characterised by extensive remodelling of the lung. Several type 2 immune cells and cytokines, including group 2 innate lymphoid cells (ILC2) and the ILC2-activating cytokine interleukin-33 (IL-33), are increased in numbers in the lung during this period. Neonatal lung ILC2 are additionally more active and responsive to stimuli than adult lung ILC2. The increase in cell numbers and activation of lung ILC2 during this period of maximal alveolarization suggests a potential role for ILC2 in postnatal lung development, yet their role is still unknown. As the lung is not fully developed at birth, early-life respiratory insults can have detrimental effects on the development of the lung. Premature birth oftentimes requires the need for supplemental oxygen, which itself can impair alveolarization due to the initiation of inflammatory responses. Similar consequences may occur after bacterial or viral respiratory tract infections in infants. These early-life insults may cause long-term deleterious changes to the developing lung and increase the susceptibility for chronic respiratory diseases in later life. Chronic respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD) are common lung diseases characterised by symptoms such as difficulty breathing, chest tightness, wheezing, and cough. In 2019, more than 260 million and 200 million people suffered from asthma and COPD, respectively, with COPD being the 3rd leading cause of death globally. Neither disease is curable, and treatments are aimed at reducing symptoms and exacerbations. Therefore, it is important to find ways to minimise risk factors for disease development. As abnormal lung development caused by, for instance, early-life respiratory insults can predispose to such chronic respiratory disease in adulthood, it is of importance to understand normal lung developmental processes in order to intervene with aberrant lung maturation. In this project, I characterised neonatal and lung ILC2, and identified how loss or gain of function of ILC2 in early life affects lung function and susceptibility to respiratory diseases in adult mice. In Chapter 3, I described the heterogeneity of mouse lung ILC2. I confirmed increased ILC2 numbers and activation in neonatal compared to adult mice and identified unique cell surface antigen expression profiles. Neonatal ILC2 were additionally characterised by increased expression of the type 2 cytokines IL-5 and IL-13, which I showed using dual-reporter mice. Moreover, I showed that female neonatal and adult mice had more lung ILC2 compared to age-matched male mice, and that lung ILC2 differed in mouse strains. The data also highlights the importance of being cautious about identifying lung ILC2 with common cell surface antigens such as ICOS or ST2 as expression changed with age and strain. In Chapter 4, I analysed the consequences of a loss of ILC2 on lung function in adulthood. To achieve this, I used ILC2-deficient mice and mice that were conditionally depleted of ILC2 in early life. In adulthood, neither ILC2-deficient nor -depleted mice displayed grossly altered lung structure, and only female ILC2-deficient mice had impaired lung function in adulthood. I also assessed the impact of increased ILC2 in early life by in vivo administration of recombinant IL-33. Early-life IL-33 administration increased lung ILC2 and induced cell surface antigen expression associated with an inflammatory ILC2 phenotype. These changes were persistent and continued into adulthood. Whilst administration of IL-33 to adult mice also increased lung ILC2 numbers, cell surface antigen expression of common ILC2 markers differed compared to ILC2 that were stimulated in early-life. This further showed that lung ILC2 have age-dependent responses to stimuli, and that early-life stimuli can have long-lasting effects. In Chapter 5, I identified how a loss or gain of function of ILC2 in early life altered responses to respiratory diseases in adulthood. ILC2 were either conditionally depleted in Icosdtr mice or expanded in C57BL/6 mice via IL-33 administration in early life. In adulthood, female mice were then exposed to IL-33 to induce type 2 airway inflammation, and male mice to bleomycin to induce alveolar damage and lung fibrosis. Adult IL-33 and bleomycin administration both successfully induced lung pathology, caused inflammation, and reduced lung function. These changes however were independent of early-life manipulation of pulmonary ILC2. In conclusion, I showed that lung ILC2 are a heterogenous population that differed with age, sex, and strain. Although early-life changes in ILC2 numbers did not alter susceptibility to respiratory diseases in adulthood in the experimental mouse models used in this project, the differences in neonatal and adult lung ILC2, and the persistent changes upon early-life stimuli warrant the need to further explore their role in lung development and disease.
- Subject
- innate lympoid cells; lung development; lung disease; ILC2
- Identifier
- http://hdl.handle.net/1959.13/1509135
- Identifier
- uon:56213
- Rights
- Copyright 2022 Svenja Loering
- Language
- eng
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