Evaluating the role of IL-17A as an orchestrator of peripheral-central cross talk in depressive symptoms
Lead Research Organisation:
University of Glasgow
Department Name: College of Medical, Veterinary, Life Sci
Abstract
Summary
Describe the research in simple terms in a way that could be publicised to a general audience. This will be made publicly available and Applicants are responsible for ensuring that the content is suitable for publication. No more than, 4000 characters including spaces and returns.
Approximately 30-40% of patients with immune-mediated inflammatory diseases (IMIDs), such as Psoriatic disease, experience depression. These negatively affect clinical outcomes, quality of life and treatment adherence. There is accumulating evidence that peripheral inflammation may contribute to the origins of depression. In particular, a) stimulation of the peripheral inflammation results in remitting-relapsing depressive symptoms b) abnormal neural connectivity linked to this depression is correlated with peripheral inflammation and c) biologic therapies targeting specific peripheral inflammation components (cytokines) improve depressive symptoms.
In this proposal, Psoriatic disease (PsD) will be our IMID exemplar. In this condition, the IL-23/IL-17 cytokine axis is central to its pathology, as proven by successful application of inhibitors to this pathway. Moreover, this axis has also recently been implicated in the neurobiology of depression in both preclinical and clinical studies.
We aim to uncover the mechanisms that underlie depression in the context of IMIDs, delivered by a focused immune intervention study examining brain circuitry using state of the art imaging in the context of exquisitely specific therapeutic immune interception in human immune disease.
We will test the hypotheses that depression is associated with changes in brain neurochemistry (glutamate) mediated by IL-17A. This in turn drives dysregulation in electrophysiology, function, and structure of brain regions central to reward and emotion. We will use high field strength (7T) magnetic resonance spectroscopy (MRS) to measure brain glutamate with the greatest available precision and magnetic resonance imaging (MRI) to fuse measures of brain function and connections (MRI) with measures of nerve firing (EEG) that will allow us to measure brain networks at optimal levels of resolution in time and space. These imaging and electrophysiological endpoints will be measured at baseline and 6 weeks in 50 PsD patients, randomised 1:1 to treatment with anti-IL17A antibody(secukinumab) or placebo. We predict that anti-IL17A treatment will be associated with reduced brain glutamate expression and amelioration of specific EEG/MRI measures which we consider mechanistic markers of depressive symptoms. In doing so we expect to inform the biological understanding of depression more generally with view to generating urgently needed novel drug targets for this major societal priority.
Describe the research in simple terms in a way that could be publicised to a general audience. This will be made publicly available and Applicants are responsible for ensuring that the content is suitable for publication. No more than, 4000 characters including spaces and returns.
Approximately 30-40% of patients with immune-mediated inflammatory diseases (IMIDs), such as Psoriatic disease, experience depression. These negatively affect clinical outcomes, quality of life and treatment adherence. There is accumulating evidence that peripheral inflammation may contribute to the origins of depression. In particular, a) stimulation of the peripheral inflammation results in remitting-relapsing depressive symptoms b) abnormal neural connectivity linked to this depression is correlated with peripheral inflammation and c) biologic therapies targeting specific peripheral inflammation components (cytokines) improve depressive symptoms.
In this proposal, Psoriatic disease (PsD) will be our IMID exemplar. In this condition, the IL-23/IL-17 cytokine axis is central to its pathology, as proven by successful application of inhibitors to this pathway. Moreover, this axis has also recently been implicated in the neurobiology of depression in both preclinical and clinical studies.
We aim to uncover the mechanisms that underlie depression in the context of IMIDs, delivered by a focused immune intervention study examining brain circuitry using state of the art imaging in the context of exquisitely specific therapeutic immune interception in human immune disease.
We will test the hypotheses that depression is associated with changes in brain neurochemistry (glutamate) mediated by IL-17A. This in turn drives dysregulation in electrophysiology, function, and structure of brain regions central to reward and emotion. We will use high field strength (7T) magnetic resonance spectroscopy (MRS) to measure brain glutamate with the greatest available precision and magnetic resonance imaging (MRI) to fuse measures of brain function and connections (MRI) with measures of nerve firing (EEG) that will allow us to measure brain networks at optimal levels of resolution in time and space. These imaging and electrophysiological endpoints will be measured at baseline and 6 weeks in 50 PsD patients, randomised 1:1 to treatment with anti-IL17A antibody(secukinumab) or placebo. We predict that anti-IL17A treatment will be associated with reduced brain glutamate expression and amelioration of specific EEG/MRI measures which we consider mechanistic markers of depressive symptoms. In doing so we expect to inform the biological understanding of depression more generally with view to generating urgently needed novel drug targets for this major societal priority.
Technical Summary
Describe the research in a manner suitable for a specialist reader. This content will be made publicly available and Applicants are responsible for ensuring that the content is suitable for publication. No more than 2000 characters, including spaces and returns.
Major depressive disorder (MDD) remains a global health problem and one where new therapeutic development has been hampered by a lack of novel and tractable molecular targets.
Immune-mediated inflammation has been highlighted as potential mechanistic pathway in a subset of those with MDD. Notably, people suffering from immune-mediated inflammatory diseases (IMIDs) experience increased levels of depression. In this proposal, Psoriatic disease (Ps) will be our IMID exemplar with over 25% of these patients reporting depression.
The IL-23/IL-17 cytokine axis is central to pathogenesis of Ps, as proven by successful application of IL-17A and IL-23p19 inhibitors but has also recently been implicated in the neurobiology of MDD in both preclinical and clinical studies. Evidence includes neuronal expression of IL17 receptors in brain regions central to reward and mood regulation, induction of depressive symptoms by IL17 and accumulation of Th17 (a key cellular source of IL17) in the brains of mice with depressive -type behaviours (learned helplessness).
We will leverage recent translational breakthroughs in IMIDs, linking these to innovative measures of neurobiology. We will test the hypotheses that depression is associated with changes in brain neurochemistry (glutamate) mediated by IL-17A. This in turn drives dysregulation in electrophysiology, function and structure of brain regions central to reward and emotion. We will use high field strength (7T) magnetic resonance imaging (MRI) to fuse measures of brain function and connections (MRI) with measures of neuronal firing (EEG) that will allow us to measure brain networks at optimal levels of resolution in time and space. We can then link this to the measures of brain chemistry with the greatest available precision.
We predict that anti-IL17A treatment will be associated with improved depression along with reduced brain glutamate expression and amelioration in EEG/MRI measures.
Major depressive disorder (MDD) remains a global health problem and one where new therapeutic development has been hampered by a lack of novel and tractable molecular targets.
Immune-mediated inflammation has been highlighted as potential mechanistic pathway in a subset of those with MDD. Notably, people suffering from immune-mediated inflammatory diseases (IMIDs) experience increased levels of depression. In this proposal, Psoriatic disease (Ps) will be our IMID exemplar with over 25% of these patients reporting depression.
The IL-23/IL-17 cytokine axis is central to pathogenesis of Ps, as proven by successful application of IL-17A and IL-23p19 inhibitors but has also recently been implicated in the neurobiology of MDD in both preclinical and clinical studies. Evidence includes neuronal expression of IL17 receptors in brain regions central to reward and mood regulation, induction of depressive symptoms by IL17 and accumulation of Th17 (a key cellular source of IL17) in the brains of mice with depressive -type behaviours (learned helplessness).
We will leverage recent translational breakthroughs in IMIDs, linking these to innovative measures of neurobiology. We will test the hypotheses that depression is associated with changes in brain neurochemistry (glutamate) mediated by IL-17A. This in turn drives dysregulation in electrophysiology, function and structure of brain regions central to reward and emotion. We will use high field strength (7T) magnetic resonance imaging (MRI) to fuse measures of brain function and connections (MRI) with measures of neuronal firing (EEG) that will allow us to measure brain networks at optimal levels of resolution in time and space. We can then link this to the measures of brain chemistry with the greatest available precision.
We predict that anti-IL17A treatment will be associated with improved depression along with reduced brain glutamate expression and amelioration in EEG/MRI measures.
