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Title: The influence of non-neuronal cholinergic signalling on the type 2 immune response
Author: Roberts, Luke Bryan
ISNI:       0000 0004 6496 2380
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Acetylcholine (ACh) is synthesised from choline and acetyl-CoA, primarily by the enzyme choline acetyltransferase (ChAT). Traditionally known as a crucial neurotransmitter synthesised and released by neurons of the central and peripheral nervous systems, in recent years there has been an increased interest in the role of ACh synthesised by alternative cells types - particularly those of the haematopoietic immune system. Non-neuronal ACh plays many important roles in the regulation of various immune responses in addition to being associated with the development of a number of disease pathologies. A significant number of animal parasitic nematode species have evolved to secrete active acetylcholinesterase enzymes (AChEs) which hydrolyse ACh and inhibit it from transducing cholinergic signals, suggestive perhaps of an attempt to immunomodulate their hosts in this way. Utilising the ChATBAC-eGFP reporter mouse (Tallini et al., 1996) immune cell populations capable of ACh production were identified, and the dynamics of their capacity to produce ACh were followed throughout type 2 immune responses generated during nematode infection (modelled using Nippostrongylus brasiliensis) or during allergic airway inflammation (modelled using an allergenic extract of the fungus Alternaria alternata). In carrying out these studies, type 2 innate lymphoid cells (ILC2) were newly identified as cholinergic cells capable of ACh synthesis and release during type 2 immune settings. The cholinergic phenotype of these cells was found to be closely associated with their activation state. Importantly, the cholinergic phenotype of pulmonary ILC2 could be induced by treatment of the cells with the alarmin cytokines IL-33 and IL-25, - IL-25 demonstrated a more potent capacity for this both in vitro and in vivo. Additionally, treatment of the cells with IL-2 greatly augmented the actions of IL-25 and IL-33 alone with regards to expression of the ILC2 cholinergic phenotype. Finally, in an attempt to understand the roles ACh may play during type 2 immunity in the lung, recombinant active and mutant-inactive forms of an AChE expressed by N. brasiliensis were generated using a yeast expression system. These were administered intranasally to female BALB/c mice during N. brasiliensis infection and during Alternaria allergen extract (ALT)-induced airway inflammation. Among the results observed, administration of active AChE significantly increased gut worm burden as well as influencing effector mechanisms such as neutrophilia, eosinophilia, type 2 cytokine production by ILC2 and alternative activation of macrophages, dependent on the model in question. The data presented in this thesis contribute to the understanding of how immune cell derived ACh may influence type 2 immunity and supports the argument that parasite AChEs may have evolved as immunomodulators of host immunity.
Supervisor: Selkirk, Murray Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral