S-25: A role for ILC2s, ILC3s and the NLRP3 inflammasome in different forms of asthma

Abstract

The lung is a gas exchange organ that contends with a large array of environmental factors, including allergens, infectious microbes and reactive oxygen species. A number of innate immune mechanisms have evolved to rapidly respond to these elements, and can mediate lung inflammation and asthma, a very heterogeneous disease with several distinct phenotypes. Indeed, several of different forms of asthma can develop independently of adaptive immunity, and appear to involve Type 2 as well as Type 3 innate lymphoid cells (ILCs), producing IL-5, IL-9, IL-13 or IL-17 and IL-22. Type 2 ILCs respond to allergen and to influenza infection, and can lead to airway hyperreactivity (AHR), a cardinal feature of asthma. In contrast, in obesity, which is associated with a steroid resistant form of severe asthma, CCR6+ Type 3 ILC3s expand in the lungs in response to IL-1β produced via the NLRP3 pathway in lung macrophages. Administration of IL-1β directly into the lungs of mice resulted in the expansion of lung ILC3s, and directly induced AHR. Furthermore, blockade of IL-1β with an IL-1 receptor antagonist reduced the number of lung ILC3 cells and abolished obesity-induced AHR in mice. Obesity-associated AHR was independent of adaptive immunity, as it occurred in obese Rag1−/− mice, and was dependent on interleukin-17A (IL-17A) and the NLRP3 inflammasome, as it did not develop in obese Il17a−/− or Nlrp3−/− mice, respectively. These studies suggest an important role for Type 2 and Type 3 ILCs in different forms of allergic and non-allergic asthma.