Cell lysis-induced leukotriene synthesis activates type-2 immunity in the lung

Project Summary/Abstract Treating, and in particular preventing, diseases requires an understanding of the mechanisms that lead to their initiation. Parasitic worms and allergens all trigger a “type 2” immune response, but how these agonists are first detected remains poorly understood. Group 2 innate lymphoid cells (ILC2s) are activated early in a type 2 immunity and coordinate downstream inflammation, but they do not directly sense worms or allergens. Instead, ILC2s are activated by signals released from their surrounding tissue, such as the cytokine interleukin(IL)-33. IL-33 is critical for airway type 2 immunity and its release has been linked to cell lysis caused by helminths and many allergens. We have discovered that leukotriene C4 (LTC4) and its metabolite LTD4 are also universally required for ILC2 activation and innate type 2 immunity in the lung. Which cells synthesize LTC4 and how this is activated by helminths or allergens remains unknown. Here we test the central hypothesis that by coordinating the release of both IL-33 and LTC4, loss of plasma membrane integrity (LPMI) serves as a unifying mechanism for the induction of type 2 immunity. First, we identify alveolar macrophages as an important source of LTC4 and study how LTC4 synthesis is regulated in these cells. Next, we examine the unique contributions of LTC4 and LTD4 to acute and long-term ILC2 function and downstream type 2 immunity. Lastly, we use novel tools to examine the link between lytic cell death and type 2 immunity in the lung. Our work promises to uncover novel mechanisms regulating induction of type 2 immunity and will therefore suggest novel therapeutic approaches to treat or prevent diseases such as asthma.