Following a stroke, systemic immunity is impaired, leading to increased risk of infection and death. Connie Wong and her colleagues shed new light on the mechanisms of stroke-associated immunosuppression (Science 334, 101–105).

The researchers hypothesized that invariant natural killer T (iNKT) cells in the liver might have a role in sensing damage in distant organs, such as the brain. In a mouse model of stroke, they showed that transient midcerebral artery occlusion (MCAO), followed by reperfusion, was associated with slowed crawling of iNKT cells in the liver vasculature, increased expression of the immunosuppressive cytokine IL-10 and bacterial infection. In contrast, ischemia-reperfusion injury in the hindlimb did not induce these effects.

When Wong et al. performed MCAO in iNKT cell–deficient mice, onset of bacterial infection was much sooner, but the brain infarct size was unchanged, indicating that iNKT cells have a key role in protection against infection after stroke. Antibiotic treatment rescued these mice from stroke-associated increased mortality.

But how does injury in the brain alter iNKT cell activity in the liver? The researchers found that administration of noradrenaline mimicked the effects of stroke on hepatic iNKT cell crawling, whereas these effects were blocked by a nonspecific β-adrenergic receptor inhibitor or by activation of iNKT cells by α-galactosylceramide (α-GalCer). Moreover, administration of α-GalCer or of the β-adrenergic receptor inhibitor markedly reduced the severity of bacterial infections in mice after MCAO, indicating that noradrenergic neurotransmitters released during brain injury can undermine systemic immunity by their direct effects on hepatic iNKT cells. The authors suggest that if these findings are extended to humans, a combination of modulating iNKT cell function and antibiotics might be a possible therapeutic strategy to reduce infection and mortality associated with stroke.