The chemokine fractalkine in patients with severe traumatic brain injury and a mouse model of closed head injury.

The potential role of the chemokine Fractalkine (CX3CL1) in the pathophysiology of traumatic brain injury (TBI) was investigated in patients with head trauma and in mice after experimental cortical contusion. In control individuals, soluble (s)Fractalkine was present at low concentrations in cerebrospinal fluid (CSF) (12.6 to 57.3 pg/mL) but at much higher levels in serum (21,288 to 74,548 pg/mL). Elevation of sFractalkine in CSF of TBI patients was observed during the whole study period (means: 29.92 to 535.33 pg/mL), whereas serum levels remained within normal ranges (means: 3,100 to 59,159 pg/mL). Based on these differences, a possible passage of sFractalkine from blood to CSF was supported by the strong correlation between blood-brain barrier dysfunction (according to the CSF-/serum-albumin quotient) and sFractalkine concentrations in CSF (R = 0.706; P < 0.01). In the brain of mice subjected to closed head injury, neither Fractalkine protein nor mRNA were found to be augmented; however, Fractalkine receptor (CX3CR1) mRNA steadily increased peaking at 1 week postinjury (P < 0.05, one-way analysis of variance). This possibly implies the receptor to be the key factor determining the action of constitutively expressed Fractalkine. Altogether, these data suggest that the Fractalkine-CX3CR1 protein system may be involved in the inflammatory response to TBI, particularly for the accumulation of leukocytes in the injured parenchyma.

CSF and serum levels of soluble fractalkine (CX3CL1) in inflammatory diseases of the nervous system.

The new CX(3)C-chemokine fractalkine (CX(3)CL1) was measured by Western blot in the cerebrospinal fluid (CSF) and serum of patients with inflammatory diseases of the peripheral and central nervous system (Bell's palsy, BP; Guillain-Barré Syndrome, GBS; multiple sclerosis, MS; viral meningitis, VM; bacterial meningitis, BM) and patients with noninflammatory neurological diseases (controls). In controls, fractalkine was detectable at low concentrations in the CSF and, at much higher levels, in serum. In all inflammatory neurological diseases under study, CSF fractalkine levels were significantly (p<0.01) increased vs. controls (BM>>GBS>VM>MS>BP>controls). In serum, fractalkine levels were significantly increased only in MS patients. The fractalkine CSF/serum ratios (a measure of the chemotactic gradient) were significantly elevated in BM, VM and GBS; furthermore, they tended to be increased in BP and to be decreased in MS. The elevated fractalkine CSF/serum ratios in diseases without CSF pleocytosis (GBS, BP) and a lack of correlation between fractalkine levels and CSF leukocyte counts suggested that soluble fractalkine is not a major chemokine in the CSF. There was no evidence of significant intrathecal production of fractalkine as the mean fractalkine indices (fractalkine CSF/serum ratio:albumin CSF/serum ratio) were <1 in all inflammatory diseases and not significantly elevated vs. controls.

Neuronal injury regulates fractalkine: relevance for HIV-1 associated dementia.

Fractalkine (FKN), a chemokine highly expressed in the central nervous system, participates in inflammatory responses operative in many brain disorders including HIV-1 associated dementia (HAD). In this report, HIV-1 progeny virions and pro-inflammatory products led to FKN production associated with neuronal injury and apoptosis. FKN was produced by neurons and astrocytes; but differentially produced by the two cell types. Laboratory tests paralleled those in infected people where cerebrospinal fluid FKN levels in HIV-1 infected cognitively impaired (n=16) patients were found to be increased when compared to infected patients without cognitive impairment (n=8, P=0.0345). These results demonstrate a possible role of FKN in HAD pathogenesis.

Increased intrathecal release of soluble fractalkine in HIV-infected patients.

The CX(3)C chemokine fractalkine is suggested to play an important role in inflammatory brain diseases, for example, because of its chemotactic properties. To investigate the release of soluble fractalkine in HIV-induced brain diseases fractalkine levels were determined in cerebrospinal fluid (CSF) and serum samples of HIV-infected patients with (n = 10) and without (n = 23) HIV-induced CNS complications, using semiquantitative Western blot analysis. Fractalkine CSF levels were significantly elevated (p < 0.05) in HIV-infected patients with CNS diseases compared with those without, and compared with HIV-negative controls (n = 23). Fractalkine serum concentrations did not differ between the two groups of HIV-infected patients, but were significantly elevated (p < 0.05) in HIV-infected patients with CNS complications compared with HIV-negative controls. Levels of fractalkine did not correlate with the CSF and serum HIV load and other CSF parameters. In one patient with HIV-associated dementia and myelopathy CSF fractalkine levels decreased on initiation of antiretroviral therapy and subsequent clinical improvement. In conclusion, intrathecal fractalkine release was observed in the majority of patients with HIV infection. The highest levels of soluble fractalkine were detected in CSF (and serum) samples of patients with HIV-induced CNS disorders. These results suggest a dysregulation of brain soluble fractalkine release during HIV infection.

Elevated levels of soluble fractalkine in active systemic lupus erythematosus: potential involvement in neuropsychiatric manifestations.

OBJECTIVE: To determine levels of the soluble form of the chemokine fractalkine (sFkn) and its receptor, CX(3)CR1, in patients with systemic lupus erythematosus (SLE) with neuropsychiatric involvement (NPSLE) and in SLE patients without neuropsychiatric involvement, and to assess their relationship with disease activity and organ damage. METHODS: Levels of sFkn in serum and cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay. Expression of Fkn and CX(3)CR1 was quantified using real-time polymerase chain reaction. Surface expression of CX(3)CR1 on peripheral blood mononuclear cells (PBMCs) was determined by flow cytometry. Disease activity and organ damage were assessed using the SLE Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index, respectively. RESULTS: Serum sFkn levels were significantly higher in patients with SLE than in patients with rheumatoid arthritis (RA) or healthy controls. In addition, significant correlations between serum sFkn levels and the SLEDAI, the SLICC/ACR Damage Index, anti-double-stranded DNA and anti-Sm antibody titers, immune complex levels (C1q), and serum complement levels (CH50) were observed. Expression of CX(3)CR1 was significantly greater in PBMCs from patients with active SLE than in those from RA patients or healthy controls. Levels of sFkn were also significantly higher in CSF from untreated patients with newly diagnosed NPSLE than in SLE patients without neuropsychiatric involvement; treatment reduced both serum and CSF levels of sFkn in patients with SLE. CONCLUSION: Soluble Fkn and CX(3)CR1 may play key roles in the pathogenesis of SLE, including the neuropsychiatric involvement. Soluble Fkn is also a serologic marker of disease activity and organ damage in patients with SLE, and its measurement in CSF may be useful for the diagnosis of NPSLE and followup of patients with NPSLE.