Neuropeptide regulation of non-redundant ILC2 responses at barrier surfaces

Emerging studies indicate that cooperation between neurons and immune cells regulates antimicrobial immunity, inflammation and tissue homeostasis. For example, a neuronal rheostat provides excitatory or inhibitory signals that control the functions of tissue-resident group 2 innate lymphoid cells (ILC2s) at mucosal barrier surfaces(1-4). ILC2s express NMUR1, a receptor for neuromedin U (NMU), which is a prominent cholinergic neuropeptide that promotes ILC2 responses(5-7). However, many functions of ILC2s are shared with adaptive lymphocytes, including the production of type 2 cytokines(8,9) and the release of tissue-protective amphiregulin (AREG)(10-12). Consequently, there is controversy regarding whether innate lymphoid cells and adaptive lymphocytes perform redundant or non-redundant functions(13-15). Here we generate a new genetic tool to target ILC2s for depletion or gene deletion in the presence of an intact adaptive immune system. Transgenic expression of iCre recombinase under the control of the mouse Nmur1 promoter enabled ILC2-specific deletion of AREG. This revealed that ILC2-derived AREG promotes non-redundant functions in the context of antiparasite immunity and tissue protection following intestinal damage and inflammation. Notably, NMU expression levels increased in inflamed intestinal tissues from both mice and humans, and NMU induced AREG production in mouse and human ILC2s. These results indicate that neuropeptide-mediated regulation of non-redundant functions of ILC2s is an evolutionarily conserved mechanism that integrates immunity and tissue protection.

Automated summary

Emerging studies have found that cooperation between neurons and immune cells plays a crucial role in regulating antimicrobial immunity, inflammation, and tissue homeostasis. Specifically, neuropeptide-mediated regulation of non-redundant functions of innate lymphoid cells (ILC2s) has been identified as an evolutionarily conserved mechanism that integrates immunity and tissue protection.