CXCR3-mediated natural killer cell infiltration exacerbates white matter injury after intracerebral haemorrhage.

Intracerebral haemorrhage (ICH), a subtype of stroke, carries a grim prognosis. The inflammatory response during the early phase of ICH is a major perpetuator of neurological damage. Recent clinical studies suggest possible participation of the CXC chemokine receptor 3 (CXCR3)-chemokine system in mediating neuroimmune crosstalk, which exacerbates neurological dysfunction and might serve as a potential therapeutic target in the management of ICH. CXCR3 is expressed by natural killer (NK) cells, which are known to be pathogenic in ICH. However, whether and how CXCR3 promotes NK cell infiltration and functioning in ICH and whether the attenuation of CXCR3 might affect neurological outcome have not been delineated. The present preclinical study has demonstrated, for the first time, the role of CXCR3 in facilitating the ingress of NK cells from the systemic compartment into the haemorrhagic brain and in causing ICH-related neurological injury. CXCR3 expression was found to be upregulated in the peri-haematomal region including the white matter tracts, with CXCR3+ leucocytes being the main contributor. When compared with wild-type mice, CXCR3 knockout mice showed splenic pooling of NK cells, suggestive of impaired systemic recruitment. Adoptive intravenous transfer of NK cells obtained from wild-type mice resulted in significantly greater cerebral homing of NK cells than after the transfer of NK cells obtained from CXCR3 knockout mice, confirming the pivotal role of CXCR3. Global CXCR3 deficiency was associated with reduced recruitment of NK cells expressing interferon-gamma (IFN-γ), the prototypic cytokine responsible for NK cell-induced inflammatory responses, in addition to better corticospinal tract integrity in the cervical spinal cord and improved neurological outcomes in terms of gross and fine motor functions. Systemic administration of AMG487, a CXCR3 antagonist, achieved the same effects. In conclusion, CXCR3, NK cells and IFN-γ operate in concert in ICH pathogenesis, and the attenuation of CXCR3 has important translational potential. Our findings present a new research direction in identifying novel strategies for mitigating the detrimental neuroinflammatory responses found in ICH and, possibly, in other neurological conditions.