A new-born’s first breath leads to the previously water-filled lungs being inflated with air. In this way, it brings sterile lung tissue into contact with the outside world for the first time. The lungs are one of the main sites of contact between the body and the outside world. As such, they are particularly prone to bacterial infections and must develop an elaborate immunological environment that provides protection against damage and foreign invaders.
Although the important role of the immune system in the lungs is well-known, we still understand very little about the immune system in these organs immediately after birth. The novel insights of the team led by Professor Sylvia Knapp at the CeMM Research Center for Molecular Medicine in Vienna and Andrew N J. McKenzie based in the MRC Laboratory of Molecular Biology in Cambridge, now fill this gap. The authors describe a wave of immune signalling triggered by a new-born’s very first breath. Further, they find that this immune response persists into adult life - with important consequences for the susceptibility of lungs to bacterial infection.
The authors started by examining the expression of a molecule called IL-33 in mouse embryos and new-born mice. IL-33 is a so-called cytokine, a molecule secreted by immune cells that then alters the behaviour of other cells in the immune system. The expression of IL-33 is known to be regulated by mechanical strain. Thus, the scientists hypothesized that the sudden intake of air into lungs with the new-born’s first breath would cause damage to the lung tissue resulting in IL-33 activation. Using a technique called ELISA, that allows detection of substances such as cytokines with the help of antibodies and detection enzymes, the authors compared the lungs from mice in the embryo stage with those of new-borns. They observed a large increase in IL-33 expression in the lungs of neonates.
The main target of IL-33 is another type of immune cell, called ILC2. ILC2, in turn, secretes its own cytokines, such as IL-13, which play important roles in protecting the lungs from infections and other damage. Using ELISA, the scientists compared mice with and without IL-33 and observed a reduction in the levels of several molecules that are known to be secreted by ILC2 cells. The authors further observed that the number of ILC2 cells increased dramatically over the first days of life. However, this was only apparent in mice that express normal levels of IL-33.
Alveolar macrophages are critical elements in the lung’s defence system against foreign substances and pathogens, and often act to promote inflammation. Such macrophages are termed M1 and are very effective at killing bacterial intruders. However, excessive levels of inflammation are harmful and compromise lung function. In response to “alternative” activation by IL-13, termed M2 activation, macrophages act in an anti-inflammatory manner, and instead trigger tissue remodelling. These two types of macrophage can be differentiated on the basis of the expression of certain characteristic markers. The authors reasoned that ILC2 cells might be promoting alternative macrophage activation through IL-13. This was the case: based on gene expression analysis, the authors determined that the IL-13 that accumulated in lungs after birth switched macrophages from M1 to M2 status. This effect is not confined to early life: when Knapp and her co-workers examined adult mice, they observed that IL-13 was also maintaining macrophages in an M2 state in these animals, and thus suppressing potentially harmful inflammation.
Knapp and her team also discovered that the IL-33/ILC2/IL-13-driven pathway comes at a price. Mice lacking IL-13 were better at clearing infectious S. pneumoniae bacteria, and could completely block the systemic spread of the pathogen. Thus, the very mechanism that ensures that daily environmental triggers do not compromise lung function has a catch: increased susceptibility to dangerous bacterial pathogens.
Article by Neysan Donnelly for AcademiaNet.(© AcademiaNet)