MRC National Institute for Medical Research, London
Science for Health
Towards a better understanding of lung inflammation
10 October 2011
Interleukin-9 (IL-9) is a cytokine that affects the activity of multiple cell types. It is implicated in lung inflammation, but its origin and function remain unclear. It is expressed at elevated levels in the lungs of asthmatic patients, and IL-9 blocking antibodies are currently in clinical trials as potential therapies for atopic disease. Similarly, in mouse models blockage of IL-9 signalling has been shown to reduce airway inflammation while specific over-expression of IL-9 in lungs results in the induction of an asthma-like phenotype. Important functions attributed to IL-9 in lung physiology are the induction of mucus production, goblet cell hyperplasia and other features of airway remodelling. Despite these suggested features of IL-9, it is still unclear how this cytokine is induced and what its cellular origins are.
Christoph Wilhelm (pictured), working in Gitta Stockinger's lab in the Division of Molecular Immunology, has generated a reporter mouse strain designed to fate map cells that have activated IL-9. Using this mouse strain he has shown that in the course of inflammatory responses in the lung induced by allergen, IL-9 production was largely restricted to innate lymphoid cells (ILC). ILC are recently discovered cells of haematopoietic origin which have some similarity to lymphoid tissue inducer (LTi) cells, notably the absence of lineage markers expressed by the currently classified haematopoetic cell types.
IL-9 has been notoriously difficult to detect in vivo, but the advantage of the IL-9 fate reporter is that it allows detection of cells that had once initiated IL-9 production even if they currently do not produce it anymore. Indeed the fate reporter identified a proportion of ILC as cells that had initiated the IL-9 program though at the time of analysis they were no longer producing this cytokine. These cells would therefore have been missed by conventional analysis based on intracellular cytokine staining. Those ILC that had lost expression of IL-9, instead switched on the cytokines IL-13 and IL-5, which are strongly implicated in allergic responses in the lung and normally attributed to a particular T cell subset, Th2. Dysregulated Th2 responses are a major cause of allergic reactions. Blockade of IL-9 production via neutralizing antibodies substantially reduced IL-13 and IL-5, suggesting that ILC may be a missing link in the regulation of Th2 responses.
Our findings indicate a previously unrecognized mechanism for the induction of IL-9 from ILCs and a potential involvement of IL-9 in allergic lung diseases via the promotion of IL-5 and IL- 13 production in ILCs. Understanding the mechanism of transient IL-9 regulation might prove essential to recognize the pathological function of IL-9 during airway inflammation. Taken together our data with an IL-9 fate reporter mouse underline the substantial plasticity and highly dynamic cytokine network in ILCs, which rivals that revealed in the adaptive immune system.
Gitta Stockinger
Original article
An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation
Christoph Wilhelm, Keiji Hirota, Benjamin Stieglitz, Jacques Van Snick, Mauro Tolaini, Katharina Lahl, Tim Sparwasser, Helena Helmby and Brigitta Stockinger (2011)
Nature Immunology, Epub ahead of print Publisher abstract.
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