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Regulation of type 2 immune responses via neuropeptides and neurotransmitters

Subject Area Immunology
Term from 2018 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 405448067
 
Final Report Year 2025

Final Report Abstract

Type 2 immune responses protect against worm infections but can become detrimental in the case of allergic diseases. Group 2 innate lymphoid cells (ILC2s) emerge as an innate source of cytokines promoting type 2 inflammation. ILC2 activation is mediated by the cytokines IL- 25, IL-33, and TSLP, and increasing evidence argues for neuronal factors, such as neuropeptides and neurotransmitters, as regulators of ILC2 activation. Neuronal regulators of ILC2s include Vasoactive intestinal Peptide (VIP) and the related neuropeptides Neuromedin U (NMU) and Neuromedin S (NMS), encoded by different genes. Using in vitro stimulation assays, we could show that an evolutionarily conserved corepeptide in NMU and NMS, which allows them to bind to the Neuromedin U receptor 1 (Nmur1), stimulated cytokine production of ILC2s. Further, NMS and NMU could promote ILC2 activation in vivo in an ILC2-intrinsic manner, including induction of downstream eosinophil recruitment. Gain-and-loss-of-function experiments demonstrated that NMS promoted type 2 inflammation in the context of helminth infection and allergic lung inflammation. The neuropeptide VIP stimulates type 2 immune responses via different pathways. VIP acts through two receptors, VIPR1 and VIPR2. VIP can promote IL-33 secretion from stromal cells expressing VIPR2. In addition, VIPR1 was expressed by epithelial and drives type 2 inflammation via regulation of epithelial cell differentiation towards tuft and goblet cells, which stimulates ILC2 and eosinophilia. Our previous published data have identified Nmur1 as a gene selectively expressed by ILC2s. Based on this knowledge, we have generated an ILC2-specific Cre deleter strain. By using this mouse strain, we genetically ablated ILC2s and demonstrated non-redundant functions of ILC2s in the presence of an otherwise functional immune system. ILC2s were required for the development of eosinophils and B1 cells. Furthermore, we could reveal important functions for the ILC2 - eosinophil axis during allergic lung inflammation and ILC2 - B1 for B cell receptor rearrangements and antibody production. Our data show that ILC2s were required for protective epithelial response, resulting in worm expulsion and provide strong evidence of non-redundant functions of ILC2 for type 2 immunity. Complementing the sensing abilities of neuronal factors, ILC2s also produce the factors themselves when activated. In this context, we could show that tryptophan hydroxylase 1 (Tph1), the rate-limiting enzyme for serotonin biosynthesis, is induced in ILC2s following activation or worm infection. Furthermore, genetic deletion of Tph1 in lymphocytes resulted in higher susceptibility to worm infection and persistent inflammation. Mechanistically, Tph1-deficient ILC2 failed to expand properly and to differentiate into inflammatory ILC2s, a subset of ILC2s elicited following worm infection, which was linked to worm resistance.

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