Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks

Abstract

Chemokines and their receptors have crucial roles in the trafficking of leukocytes, and are of particular interest in the context of the unique immune responses elicited in the central nervous system (CNS). The chemokine system CC ligand 2 (CCL2) with its receptor CC receptor 2 (CCR2), as well as the receptor CXCR2 and its multiple ligands CXCL1, CXCL2 and CXCL8, have been implicated in a wide range of neuropathologies, including trauma, ischemic injury and multiple sclerosis. This review aims to overview the current understanding of chemokines as mediators of leukocyte migration into the CNS under neuroinflammatory conditions. We will specifically focus on the involvement of two chemokine networks, namely CCL2/CCR2 and CXCL8/CXCR2, in promoting macrophage and neutrophil infiltration, respectively, into the lesioned parenchyma after focal traumatic brain injury. The constitutive brain expression of these chemokines and their receptors, including their recently identified roles in the modulation of neuroprotection, neurogenesis, and neurotransmission, will be discussed. In conclusion, the value of evidence obtained from the use of Ccl2- and Cxcr2-deficient mice will be reported, in the context of potential therapeutics inhibiting chemokine activity which are currently in clinical trial for various inflammatory diseases.

Figure 1

Effect of chemokine ligand or receptor deficiency on leukocyte infiltration after experimental focal traumatic brain injury. Upper microscope images illustrate the accumulation of macrophages and activated microglia in the injured cortex at 4 weeks after closed head injury, which was considerably reduced in Ccl2−/− mice (panel B) compared with wild-type controls (panel A). Lower images show the influx of neutrophils peaking at 12 h after injury in wild-type mice (panel C). In contrast, few neutrophils are able to infiltrate the brains of Cxcr2−/− mice (panel D). Stainings were performed with monoclonal anti-mouse F4/80 and NIMP-R14 antibodies (Serotec, Raleigh, NC, USA), for macrophages/microglia and neutrophils, respectively. Scale bar (panels A and B)=200 μm; (panels C and D)=500 μm. Unpublished data are obtained from the study by BD. Semple.

Figure 2

The roles of CCL2/CCR2 in brain inflammation and injury. CCL2 induces the recruitment of macrophages, production of cytokines, and direct alteration of the expression of endothelial cell tight-junction proteins to increase blood–brain barrier (BBB) permeability, which contributes to inflammation in the brain, potentially exacerbating neuronal loss. CCL2-mediated macrophage accumulation may also be beneficial, as these phagocytic cells remove myelin debris, which otherwise inhibits regeneration. Furthermore, CCL2 is chemotactic for neural precursor cells and thus, may influence repair after injury by enhancing neurogenesis.

Figure 3

The multiple functions mediated by CXCR2 signaling in the CNS. CXCR2 is the main receptor involved in neutrophil chemotaxis, leading to cell migration into the brain during injury, infection or disease. Neutrophils perpetuate the neuroinflammatory response by the release of enzymes such as proteases, contributing to neuronal degeneration. Independent of this role, CXCR2 signaling is involved in chemotaxis of oligodendrocyte precursors during development, the release of growth factors, mediating self-defense mechanisms against Fas-initiated apoptotic cell death, and modulating synaptic transmission through altering calcium channel excitability and neurotransmitter release.