Increased brain damage after ischaemic stroke in mice lacking the chemokine receptor CCR5

Abstract

Background and purpose:The chemokine receptor CCR5 is well known for its function in immune cells; however, it is also expressed in the brain, where its specific role remains to be elucidated. Because genetic factors may influence the risk of developing cerebral ischaemia or affect its clinical outcome, we have analysed the role of CCR5 in experimental stroke. Experimental approach: Permanent cerebral ischaemia was performed by occlusion of the middle cerebral artery in wild-type and CCR5-deficient mice. Locomotor behaviour, infarct size and histochemical alterations were analysed at different time points after occlusion. Key results: The cerebral vasculature was comparable in wild-type and CCR5-deficient mice. However, the size of the infarct and the motor deficits after occlusion were markedly increased in CCR5-deficient mice as compared with wild type. No differences between wild-type and CCR5-deficient mice were elicited by occlusion with respect to the morphology and abundance of astrocytes and microglia. Seven days after occlusion the majority of CCR5-deficient mice displayed neutrophil invasion in the infarct region, which was not observed in wild type. As compared with wild type, the infarct regions of CCR5-deficient mice were characterized by increased neuronal death. Conclusions and implications:Lack of CCR5 increased the severity of brain injury following occlusion of the middle cerebral artery. This is of particular interest with respect to the relatively frequent occurrence of CCR5 deficiency in the human population (1-2% of the Caucasian population) and the advent of CCR5 inhibitors as novel drugs.

Chemokines in CNS injury and repair

“…Moreover, mice carrying mutations of CCR5, the receptor for chemokines CCL3, CCL4, CCL5, CCL8, CCL11, CCL14 and CCL16, show larger cerebral infarct size, with increased neuronal death and neutrophil infiltration associated with behavioural deficits (Sorce et al 2010). The mechanism by which CCR5 reduces secondary damage after CNS injury is not known, although both direct effects on neurons and avoidance of excessive microglial activation have been considered.…”

Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals

“…Of note chemokines and their receptors (such as CCR5) are suggested to be involved in physiological neuroglial communication (Park et al , 2009), neuronal differentiation (Park et al , 2009), and neuronal survival under pro-apoptotic conditions (Meucci et al , 1998). Further, loss of dopaminergic neurons (Choi et al , 2013) and increased brain damage after ischemic stroke (Sorce et al , 2010) has been reported in CCR5-deficient mice. Thus, under certain conditions, loss of CCR5 function (i.e.…”

CCR5 deficiency increased susceptibility to lipopolysaccharide-induced acute renal injury

“…CCR5 knockout mice showed increased mortality rates in the pulmonary inflammatory response to influenza A virus infection, which involved accelerated macrophage accumulation in the lung (Dawson et al 2000). Furthermore, CCR5-deficient mice showed increased severity of brain damage after ischemic stroke, which involved increased neutrophil infiltration in the brain (Sorce et al 2010).…”