The role of CXC chemokine receptor 3 in modulating neuroimmune responses and functional outcomes after experimental intracerebral haemorrhage

Abstract

Intracerebral haemorrhage (ICH) is a subtype of stroke with high mortality and morbidity rates. Despite continuous research efforts, no treatment modality that improves clinical prognosis is available currently. Such failure can be the consequence of incomplete understanding of the complex pathophysiology. Multiple components, including neuroinflammation, are involved in secondary brain injury after the initial haemorrhagic event. Recent clinical and preclinical studies have yielded more information about neuroimmune cross- talk in ICH, particularly the role of peripheral immunity. Chemokine- chemokine receptor systems are major channels that relay signals between the systemic and central nervous system (CNS) compartments. The correlations between some chemokines and clinical outcomes of ICH support the involvement of chemokine- chemokine receptor systems in the pathogenesis. The participation of certain leukocyte subpopulations can be predicted based on these clinical associations as leukocyte subsets respond to distinct chemokines via expressing the corresponding receptors. Yet, the effects of modulating the components of chemokine- receptor axes on the immune response to and outcomes of ICH have not been characterized in detail.

Chemokine (C-X-C motif) receptor 3 (CXCR3) is a chemokine receptor that binds to several ligands. It is known to be expressed mainly by leukocytes of the lymphoid lineage but also by a wide range of cells thus context- specificity is an important feature in terms of its functions. Nevertheless, regulation of immune cell activities is a major property of CXCR3. The upregulation of one of the CXCR3 ligands has been associated with poor clinical outcomes of ICH. However, the relative significance of CXCR3 in pathogenesis is unknown. As leukocyte subsets contributing to secondary brain damage in ICH have been independently shown to express CXCR3, signalling via this receptor may be involved in modulating the immune response along with functional outcomes.

This preclinical study, for the first time, examined the in vivo effects of inhibiting and knocking out CXCR3 on ICH outcomes during the first week after onset. Experimental ICH was first induced in mice by intra- striatal injection of type IV collagenase. Subsequent investigation included the delineation of the temporal pattern of CXCR3 expression, the identification of CXCR3- expressing cell types, and functional assessment of CXCR3 via global depletion of its expression. Improvement in ICH outcomes including better motor functions and less severe white matter injury seen in the CXCR3- deficient mice might be partially mediated by the attenuated response of natural killer (NK) cells to ICH following CXCR3 depletion. Specifically, the expression of interferon- gamma (IFN- γ), an inflammatory cytokine, and the accumulation of NK cells were reduced. Furthermore, the systemic administration of a CXCR3 antagonist replicated the behavioural recovery to a similar extent. These results suggest that the harmful effects of CXCR3 on the aftermath of ICH can be reduced by CXCR3 deficiency as well as antagonism.

In summary, this project is the very first to reveal CXCR3- mediated immune response in ICH. Inhibition of the CXCR3 system may be applied clinically for the treatment of ICH after extensive research in the future.