Evaluating the role of IL-17A as an orchestrator of peripheral-central cross talk in depressive symptoms

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SummaryDescribe 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.