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Possible role of glial cells in the onset and progression of Lyme neuroborreliosis.

Ramesh G, Borda JT, Gill A, Ribka EP, Morici LA, Mottram P, Martin DS, Jacobs MB, Didier PJ, Philipp MT - J Neuroinflammation (2009)

Bottom Line: CCL2 and CXCL13 were found in microglia as well as in endothelial cells, macrophages and T cells.Importantly, the DRG of infected animals showed significant satellite cell and neuronal apoptosis.Our results support the notion that innate responses of glia to B. burgdorferi initiate/mediate the inflammation seen in acute LNB, and show that neuronal apoptosis occurs in this context.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Covington, LA, USA. gramesh@tulane.edu

ABSTRACT

Background: Lyme neuroborreliosis (LNB) may present as meningitis, cranial neuropathy, acute radiculoneuropathy or, rarely, as encephalomyelitis. We hypothesized that glia, upon exposure to Borrelia burgdorferi, the Lyme disease agent, produce inflammatory mediators that promote the acute cellular infiltration of early LNB. This inflammatory context could potentiate glial and neuronal apoptosis.

Methods: We inoculated live B. burgdorferi into the cisterna magna of rhesus macaques and examined the inflammatory changes induced in the central nervous system (CNS), and dorsal root nerves and ganglia (DRG).

Results: ELISA of the cerebrospinal fluid (CSF) showed elevated IL-6, IL-8, CCL2, and CXCL13 as early as one week post-inoculation, accompanied by primarily lymphocytic and monocytic pleocytosis. In contrast, onset of the acquired immune response, evidenced by anti-B. burgdorferi C6 serum antibodies, was first detectable after 3 weeks post-inoculation. CSF cell pellets and CNS tissues were culture-positive for B. burgdorferi. Histopathology revealed signs of acute LNB: severe multifocal leptomeningitis, radiculitis, and DRG inflammatory lesions. Immunofluorescence staining and confocal microscopy detected B. burgdorferi antigen in the CNS and DRG. IL-6 was observed in astrocytes and neurons in the spinal cord, and in neurons in the DRG of infected animals. CCL2 and CXCL13 were found in microglia as well as in endothelial cells, macrophages and T cells. Importantly, the DRG of infected animals showed significant satellite cell and neuronal apoptosis.

Conclusion: Our results support the notion that innate responses of glia to B. burgdorferi initiate/mediate the inflammation seen in acute LNB, and show that neuronal apoptosis occurs in this context.

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Related in: MedlinePlus

Early appearance of cytokines and chemokines in the CSF. Levels of IL-6 (A), IL-8 (B), CCL2 (C) and CXCL13 (D) in the CSF of all of the animals in the study as a function of time PI. The dotted line represents the cut-off value obtained as described in Materials and Methods. Data represent the mean ± SD of duplicate determinations except for CXCL13, where availability of CSF only permitted duplicate determinations for all data points of animal DH50, and some data points of animals DR50 and CH82.
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Figure 2: Early appearance of cytokines and chemokines in the CSF. Levels of IL-6 (A), IL-8 (B), CCL2 (C) and CXCL13 (D) in the CSF of all of the animals in the study as a function of time PI. The dotted line represents the cut-off value obtained as described in Materials and Methods. Data represent the mean ± SD of duplicate determinations except for CXCL13, where availability of CSF only permitted duplicate determinations for all data points of animal DH50, and some data points of animals DR50 and CH82.

Mentions: CSF from infected animals showed levels above the cut-off value for the cytokine IL-6 in animals DR50, EL81 and DH50, between week 1–3 (Fig 2a). Animal EP51 showed levels of IL-6 just exceeding the cut-off value at weeks 1 and 2 PI. The chemokine IL-8 was significantly elevated in the CSF of all of the inoculated animals (Fig 2b), reaching maximum levels ranging from 10.9 to 35 pg/ml between weeks 1 and 2 PI. Monocyte chemoattractant protein-1MCP-1/CCL2 was significantly elevated in all of the infected animals (Fig 2c) except CH82, ranging between 350 pg/ml to 500 pg/ml by week 2 PI. The levels of IL-6 in the CSF were higher than those observed in the serum of all of the infected animals, except CH82, (Table 3), indicating that this cytokine was produced primarily intrathecally. On the other hand, IL-8 levels were much higher in serum than they were in CSF (Table 3). The levels of CCL2 were considerably higher in the CSF compared to those found at the corresponding time points in serum, suggesting, once again, a predominantly CNS origin for this chemokine. The concentration of the B-lymphocyte chemokine CXCL13/BLC was elevated above the cut-off value in animals DR50, DH50, EL81, and EP51, reaching peak values of around 5500 pg/ml between weeks 2 and 4 PI (Fig 2d). The CSF levels of CXCL13 were higher in three out of four of the inoculated animals (DR50, EL81, and DH50) as compared to those in paired serum specimens (Table 3), implying a possible CNS origin for this mediator as well. The very early appearance of inflammatory mediators (week 1–2 PI) in the CSF indicates that innate immune responses are at play. In addition, the very high serum concentrations of IL-8 detected as early as week 1 PI, much higher than the corresponding CSF levels, are data to suggest that the infection became systemic soon after the intrathecal inoculation.


Possible role of glial cells in the onset and progression of Lyme neuroborreliosis.

Ramesh G, Borda JT, Gill A, Ribka EP, Morici LA, Mottram P, Martin DS, Jacobs MB, Didier PJ, Philipp MT - J Neuroinflammation (2009)

Early appearance of cytokines and chemokines in the CSF. Levels of IL-6 (A), IL-8 (B), CCL2 (C) and CXCL13 (D) in the CSF of all of the animals in the study as a function of time PI. The dotted line represents the cut-off value obtained as described in Materials and Methods. Data represent the mean ± SD of duplicate determinations except for CXCL13, where availability of CSF only permitted duplicate determinations for all data points of animal DH50, and some data points of animals DR50 and CH82.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2748066&req=5

Figure 2: Early appearance of cytokines and chemokines in the CSF. Levels of IL-6 (A), IL-8 (B), CCL2 (C) and CXCL13 (D) in the CSF of all of the animals in the study as a function of time PI. The dotted line represents the cut-off value obtained as described in Materials and Methods. Data represent the mean ± SD of duplicate determinations except for CXCL13, where availability of CSF only permitted duplicate determinations for all data points of animal DH50, and some data points of animals DR50 and CH82.
Mentions: CSF from infected animals showed levels above the cut-off value for the cytokine IL-6 in animals DR50, EL81 and DH50, between week 1–3 (Fig 2a). Animal EP51 showed levels of IL-6 just exceeding the cut-off value at weeks 1 and 2 PI. The chemokine IL-8 was significantly elevated in the CSF of all of the inoculated animals (Fig 2b), reaching maximum levels ranging from 10.9 to 35 pg/ml between weeks 1 and 2 PI. Monocyte chemoattractant protein-1MCP-1/CCL2 was significantly elevated in all of the infected animals (Fig 2c) except CH82, ranging between 350 pg/ml to 500 pg/ml by week 2 PI. The levels of IL-6 in the CSF were higher than those observed in the serum of all of the infected animals, except CH82, (Table 3), indicating that this cytokine was produced primarily intrathecally. On the other hand, IL-8 levels were much higher in serum than they were in CSF (Table 3). The levels of CCL2 were considerably higher in the CSF compared to those found at the corresponding time points in serum, suggesting, once again, a predominantly CNS origin for this chemokine. The concentration of the B-lymphocyte chemokine CXCL13/BLC was elevated above the cut-off value in animals DR50, DH50, EL81, and EP51, reaching peak values of around 5500 pg/ml between weeks 2 and 4 PI (Fig 2d). The CSF levels of CXCL13 were higher in three out of four of the inoculated animals (DR50, EL81, and DH50) as compared to those in paired serum specimens (Table 3), implying a possible CNS origin for this mediator as well. The very early appearance of inflammatory mediators (week 1–2 PI) in the CSF indicates that innate immune responses are at play. In addition, the very high serum concentrations of IL-8 detected as early as week 1 PI, much higher than the corresponding CSF levels, are data to suggest that the infection became systemic soon after the intrathecal inoculation.

Bottom Line: CCL2 and CXCL13 were found in microglia as well as in endothelial cells, macrophages and T cells.Importantly, the DRG of infected animals showed significant satellite cell and neuronal apoptosis.Our results support the notion that innate responses of glia to B. burgdorferi initiate/mediate the inflammation seen in acute LNB, and show that neuronal apoptosis occurs in this context.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Covington, LA, USA. gramesh@tulane.edu

ABSTRACT

Background: Lyme neuroborreliosis (LNB) may present as meningitis, cranial neuropathy, acute radiculoneuropathy or, rarely, as encephalomyelitis. We hypothesized that glia, upon exposure to Borrelia burgdorferi, the Lyme disease agent, produce inflammatory mediators that promote the acute cellular infiltration of early LNB. This inflammatory context could potentiate glial and neuronal apoptosis.

Methods: We inoculated live B. burgdorferi into the cisterna magna of rhesus macaques and examined the inflammatory changes induced in the central nervous system (CNS), and dorsal root nerves and ganglia (DRG).

Results: ELISA of the cerebrospinal fluid (CSF) showed elevated IL-6, IL-8, CCL2, and CXCL13 as early as one week post-inoculation, accompanied by primarily lymphocytic and monocytic pleocytosis. In contrast, onset of the acquired immune response, evidenced by anti-B. burgdorferi C6 serum antibodies, was first detectable after 3 weeks post-inoculation. CSF cell pellets and CNS tissues were culture-positive for B. burgdorferi. Histopathology revealed signs of acute LNB: severe multifocal leptomeningitis, radiculitis, and DRG inflammatory lesions. Immunofluorescence staining and confocal microscopy detected B. burgdorferi antigen in the CNS and DRG. IL-6 was observed in astrocytes and neurons in the spinal cord, and in neurons in the DRG of infected animals. CCL2 and CXCL13 were found in microglia as well as in endothelial cells, macrophages and T cells. Importantly, the DRG of infected animals showed significant satellite cell and neuronal apoptosis.

Conclusion: Our results support the notion that innate responses of glia to B. burgdorferi initiate/mediate the inflammation seen in acute LNB, and show that neuronal apoptosis occurs in this context.

Show MeSH
Related in: MedlinePlus