The neuronal chemokine CX3CL1/fractalkine selectively recruits NK cells that modify experimental autoimmune encephalomyelitis within the central nervous system

Abstract

Leukocyte trafficking to the central nervous system (CNS), regulated in part by chemokines, determines severity of the demyelinating diseases multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). To examine chemokine receptor CX3CR1 in EAE, we studied CX3CR1(GFP/GFP) mice, in which CX3CR1 targeting by insertion of Green Fluorescent Protein (GFP) allowed tracking of CX3CR1+ cells in CX3CR1(+/GFP) animals and cells destined to express CX3CR1 in CX3CR1(GFP/GFP) knockouts. NK cells were markedly reduced in the inflamed CNS of CX3CR1-deficient mice with EAE, whereas recruitment of T cells, NKT cells and monocyte/macrophages to the CNS during EAE did not require CX3CR1. Impaired recruitment of NK cells in CX3CR1(GFP/GFP) mice was associated with increased EAE-related mortality, nonremitting spastic paraplegia and hemorrhagic inflammatory lesions. The absence of CD1d did not affect the severity of EAE in CX3CR1(GFP/GFP) mice, arguing against a role for NKT cells. Accumulation of NK cells in livers of wild-type (WT) and CX3CR1(GFP/GFP) mice with cytomegalovirus hepatitis was equivalent, indicating that CX3CL1 mediated chemoattraction of NK cells was relatively specific for the CNS. These results are the first to define a chemokine that governs NK cell migration to the CNS, and the findings suggest novel therapeutic manipulation of CX3CR1+ NK cells.

Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, or Reduce?

“…EAE in CX3CR1 Ϫ/Ϫ mice showed exaggerated disease severity, associated with an impairment of the migration of regulatory NK cells to the CNS. 88 These results, and corollary studies, suggest a protective role of NK cells during EAE, and showed further that CX3CL1-CX3CR1 govern the migration of these cells to the CNS, but not to the liver.…”

Adenosine A1 Receptors and Microglial Cells Mediate CX3CL1-Induced Protection of Hippocampal Neurons Against Glu-Induced Death

“…It is proposed that microglia has a prominent role in mediating the neuroprotective effects of CX3CL1 (Mizuno et al, 2003;Huang et al, 2006;Cardona et al, 2006) and we have recently shown that CX3CL1-stimulated microglia releases neuroprotective substances that reduce Glu-induced cell death (Lauro et al, 2008). However CX3CL1 does not protect against all types of neuronal damage because in transient brain ischemia (Soriano et al, 2002;Dénes et al, 2008) and in a rat model of Parkinson's disease, intrastriatal CX3CL1 injection induced both microglia-dependent depletion of dopaminergic cells and motor dysfunction (Shan et al, 2009).…”

“…CX3CL1 is constitutively expressed in the nervous system, but levels in the brain can be modulated under diverse pathological conditions (Pan et al, 1997;Hughes et al, 2002;Kastenbauer et al, 2003;Sunnemark et al, 2005;Huang et al, 2006). The presence and the stimulation (Zujovic et al, 2000(Zujovic et al, , 2001Mizuno et al, 2003;Cardona et al, 2006;Lyons et al, 2009) of the CX3CL1 receptor CX3CR1 has been correlated with a reduced release of interleukin-1-b (IL-1-b) and tumor necrosis factor-a (TNF-a) from microglial cells and a lower rate of neuronal degeneration in different experimental models of neuropathologies such as experimental autoimmune encephalomyelitis, 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine hydrochloride striatal injection, lipopolysaccharide administration, and superoxide dismutase (SOD1) mutation (Huang et al, 2006;Cardona et al, 2006). These data attest to a role of the pair CX3CL1/CX3CR1 in reducing neuronal degeneration on several types of brain injury.…”

Identification of Chemoattractive Factors Involved in the Migration of Bone Marrow-Derived Mesenchymal Stem Cells to Brain Lesions Caused by Prions

“…Although neuroprotective functions of MSCs that have migrated to brain lesions are not fully understood, the temporal and spatial differences in the expression of chemokine receptors on hMSCs transplanted into the brains of prion-infected mice that we observed in the present study is intriguing, i.e., hMSCs that are considered to be in the process of migration in the corpus callosum expressed CCR3, CCR5, and CXCR3, whereas hMSCs that had migrated to the target site showed reduced expression of these receptors but elevated expression of CCR1 and CX3CR1. The stimulation of CX3CR1 by its ligand CX3CL1 plays a role in modulating the release of proinflammatory cytokines from microglia (7,21) and in producing neuroprotective substances (31). Therefore, the expression of CX3CR1 on MSCs that had migrated to the contralateral hippocampus might be an indicator of functional alteration of hMSCs, i.e., alteration from active migration toward the target site to exhibition of neuroprotective potential.…”