Interleukin-1 in brain haemorrhage and ischaemia

UoM administered thesis: Phd

Abstract

Stroke is a major global health burden with limited therapeutic options. Two major subtypes of stroke exist, ischaemic stroke (IS) and intracerebral haemorrhage (ICH). IS occurs following cerebrovascular occlusion, whereas ICH occurs when a vessel bursts and blood enters parenchymal brain tissue. The acute inflammatory response to both of these subtypes is thought to exacerbate neuronal injury and contribute to poor patient outcomes. The prototypical cytokine interleukin-1 (IL-1) sits at the apex of many inflammatory processes and a substantial amount of preclinical evidence strongly implicates IL-1 in IS pathogenesis. However, despite this, it is currently unclear whether IL-1 contributes to ICH pathophysiology. Thus, the primary aim of this doctoral thesis was to determine the contribution of IL-1 to ICH. Further, the canonical IL-1 family is composed of two distinct proteins, IL-1a and IL-1b, which require proteolytic processing to activate the IL-1 receptor. Therefore, the secondary aim of this doctoral thesis was to further our understanding of the active IL-1 proteolytic processing pathways in IS and ICH. Initial work carried out for this thesis refined the collagenase-induced mouse model of ICH to reduce animal usage and suffering. This refined model was subsequently used to uncover novel dichotomous actions of IL-1 in ICH. Using RNA sequencing, IL-1 was revealed as the major upstream regulator of cerebral inflammation that controlled harmful monocyte trafficking to the haemorrhaged brain. However, inhibition of IL-1 actually worsened neuromotor injury following ICH by preventing an IL-1-dependent increase in cerebral blood flow to the affected hemisphere. IL-1b was the predominant IL-1 molecule produced in ICH, but inhibition of the IL-1b processing enzyme, caspase-1, showed this pathway was not necessary for immune recruitment. Similarly, pharmacological and genetic targeting of the NLRP3 inflammasome, which sits upstream of caspase-1 activation, did not affect inflammation or lesion size in a clot-induced mouse model of IS. Overall this thesis exposes novel actions of IL-1 in ICH. Whilst IL-1 appears to be a major upstream regulator of harmful immune recruitment in both IS and ICH, it may also positively regulate cerebral blood flow in ICH. Therefore, future work should build upon the findings in this thesis and segregate the downstream molecular mechanisms governing IL-1s beneficial and harmful effects, in order to provide novel therapeutic targets for both stroke subtypes.

Details

Original languageEnglish
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Award date1 Aug 2020