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Immune to brain communication in allergic lung inflammation

Immune to brain communication in allergic lung inflammation
Immune to brain communication in allergic lung inflammation
Asthma, a chronic TH2-mediated inflammatory disease of the airways, is the most common form of allergy in the Western world, affecting 300 million people worldwide. Epidemiological studies have shown that asthma is associated with mood disorders, such as anxiety and depression, and numerous experiments have reported that asthma induces functional changes in neuronal fibres of the peripheral nervous system (PNS), which innervate the brain. It is unknown, however, how allergic lung inflammation impacts on the central nervous system (CNS). The ability for peripheral inflammation to impact on the brain, altering behaviour and neuronal activity in the CNS, is a well-recognised and physiological phenomenon, known as immune to brain communication, but has, until now, only focused on how innate pro-inflammatory and TH1, but not TH2, type immune responses impact on the brain. Critically, immunomodulatory therapeutics, which involve stimulation of an innate pro-inflammatory immune response, are currently being developed for the treatment of asthma, highlighting the importance of understanding the effect of allergic lung inflammation and its treatment on the brain. Consequently, using acute and chronic localised TH2 models of inflammation, we investigated how allergic lung inflammation impacted on the CNS and subsequently determined the secondary impact of immunomodulation with the Toll-like receptor 7 (TLR7) agonist resiquimod.
Acute TH2 inflammation in the peritoneum and lung was found to communicate with the brain, via a vagal route of communication. Crucially, it led to a distinct pattern of neuronal activity, with no changes in sickness behaviour or CNS inflammation, changes widely different to those known to occur following systemic TH1 inflammation. At chronic stages of lung inflammation, changes in genes associated with synaptic plasticity in the brainstem and altered expression of the GABAB receptor and brain-derived neurotrophic factor in the hippocampus were observed, firstly providing a CNS-dependent biological explanation for airway hyperresponsiveness, a critical pathological symptom of asthma, and secondly offering a biological justification for the prevalence of mood disorders in asthmatic patients. Resiquimod treatment in allergic animals was associated with attenuated central inflammatory responses, as compared to treatment in healthy animals, encouraging and reassuring in terms of patient well-being and, critically, also insinuating that safety of therapeutics differs in diseased, as opposed to healthy individuals. The results in this thesis are some of the first to identify that physiological inflammatory diseases impact on the CNS, highlighting the importance of immune to brain communication on pathological and psychopathological symptoms of a disease, and additionally demonstrating how inflammatory conditions can modify the off-target effects of a drug. Not only do these results provide a foundation for the future of immune to brain communication research, namely understanding how physiological inflammatory diseases impact on the CNS, but also have the potential to be translational and emulated in a clinical setting.
Larsson, Emelie Olivia
85f6ae13-a382-47ce-951e-956509035232
Larsson, Emelie Olivia
85f6ae13-a382-47ce-951e-956509035232
Teeling, Jessica
fcde1c8e-e5f8-4747-9f3a-6bdb5cd87d0a

(2013) Immune to brain communication in allergic lung inflammation. University of Southampton, Biological Sciences, Doctoral Thesis, 279pp.

Record type: Thesis (Doctoral)

Abstract

Asthma, a chronic TH2-mediated inflammatory disease of the airways, is the most common form of allergy in the Western world, affecting 300 million people worldwide. Epidemiological studies have shown that asthma is associated with mood disorders, such as anxiety and depression, and numerous experiments have reported that asthma induces functional changes in neuronal fibres of the peripheral nervous system (PNS), which innervate the brain. It is unknown, however, how allergic lung inflammation impacts on the central nervous system (CNS). The ability for peripheral inflammation to impact on the brain, altering behaviour and neuronal activity in the CNS, is a well-recognised and physiological phenomenon, known as immune to brain communication, but has, until now, only focused on how innate pro-inflammatory and TH1, but not TH2, type immune responses impact on the brain. Critically, immunomodulatory therapeutics, which involve stimulation of an innate pro-inflammatory immune response, are currently being developed for the treatment of asthma, highlighting the importance of understanding the effect of allergic lung inflammation and its treatment on the brain. Consequently, using acute and chronic localised TH2 models of inflammation, we investigated how allergic lung inflammation impacted on the CNS and subsequently determined the secondary impact of immunomodulation with the Toll-like receptor 7 (TLR7) agonist resiquimod.
Acute TH2 inflammation in the peritoneum and lung was found to communicate with the brain, via a vagal route of communication. Crucially, it led to a distinct pattern of neuronal activity, with no changes in sickness behaviour or CNS inflammation, changes widely different to those known to occur following systemic TH1 inflammation. At chronic stages of lung inflammation, changes in genes associated with synaptic plasticity in the brainstem and altered expression of the GABAB receptor and brain-derived neurotrophic factor in the hippocampus were observed, firstly providing a CNS-dependent biological explanation for airway hyperresponsiveness, a critical pathological symptom of asthma, and secondly offering a biological justification for the prevalence of mood disorders in asthmatic patients. Resiquimod treatment in allergic animals was associated with attenuated central inflammatory responses, as compared to treatment in healthy animals, encouraging and reassuring in terms of patient well-being and, critically, also insinuating that safety of therapeutics differs in diseased, as opposed to healthy individuals. The results in this thesis are some of the first to identify that physiological inflammatory diseases impact on the CNS, highlighting the importance of immune to brain communication on pathological and psychopathological symptoms of a disease, and additionally demonstrating how inflammatory conditions can modify the off-target effects of a drug. Not only do these results provide a foundation for the future of immune to brain communication research, namely understanding how physiological inflammatory diseases impact on the CNS, but also have the potential to be translational and emulated in a clinical setting.

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More information

Published date: 31 March 2013
Organisations: University of Southampton, Centre for Biological Sciences

Identifiers

Local EPrints ID: 355709
URI: http://eprints.soton.ac.uk/id/eprint/355709
PURE UUID: b2a3b48e-2b68-4098-a40a-9e88aa4fa32f
ORCID for Jessica Teeling: ORCID iD orcid.org/0000-0003-4004-7391

Catalogue record

Date deposited: 12 Nov 2013 16:20
Last modified: 19 Jun 2019 00:35

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Contributors

Author: Emelie Olivia Larsson
Thesis advisor: Jessica Teeling ORCID iD

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