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Fcγ receptor-mediated inflammation inhibits axon regeneration.

Zhang G, Bogdanova N, Gao T, Song JJ, Cragg MS, Glennie MJ, Sheikh KA - PLoS ONE (2014)

Bottom Line: Anti-glycan/ganglioside antibodies are the most common immune effectors found in patients with Guillain-Barré Syndrome, which is a peripheral autoimmune neuropathy.These findings have clinical implications for nerve repair and recovery in antibody-mediated immune neuropathies.Our results add to the complexity of axon regeneration in injured peripheral and central nervous systems as adverse effects of B cells and autoantibodies on neural injury and repair are increasingly recognized.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Texas Medical School at Houston, Houston, Texas, United States of America.

ABSTRACT
Anti-glycan/ganglioside antibodies are the most common immune effectors found in patients with Guillain-Barré Syndrome, which is a peripheral autoimmune neuropathy. We previously reported that disease-relevant anti-glycan autoantibodies inhibited axon regeneration, which echo the clinical association of these antibodies and poor recovery in Guillain-Barré Syndrome. However, the specific molecular and cellular elements involved in this antibody-mediated inhibition of axon regeneration are not previously defined. This study examined the role of Fcγ receptors and macrophages in the antibody-mediated inhibition of axon regeneration. A well characterized antibody passive transfer sciatic nerve crush and transplant models were used to study the anti-ganglioside antibody-mediated inhibition of axon regeneration in wild type and various mutant and transgenic mice with altered expression of specific Fcγ receptors and macrophage/microglia populations. Outcome measures included behavior, electrophysiology, morphometry, immunocytochemistry, quantitative real-time PCR, and western blotting. We demonstrate that the presence of autoantibodies, directed against neuronal/axonal cell surface gangliosides, in the injured mammalian peripheral nerves switch the proregenerative inflammatory environment to growth inhibitory milieu by engaging specific activating Fcγ receptors on recruited monocyte-derived macrophages to cause severe inhibition of axon regeneration. Our data demonstrate that the antibody orchestrated Fcγ receptor-mediated switch in inflammation is one mechanism underlying inhibition of axon regeneration. These findings have clinical implications for nerve repair and recovery in antibody-mediated immune neuropathies. Our results add to the complexity of axon regeneration in injured peripheral and central nervous systems as adverse effects of B cells and autoantibodies on neural injury and repair are increasingly recognized.

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Anti-glycan Ab-mediated inhibition of axon regeneration was independent of activating FcγRIV.Sciatic nerve micrographs from Fcgr4- mice treated with sham Ab or GD1a/GT1b-2b mAb (A). MF counts in sciatic (B) or tibial (C) nerves from WT or Fcgr4- mice treated with sham Ab or GD1a/GT1b-2b mAb. Quantitative electrophysiological data showing CMAP amplitudes of WT or Fcgr4- mice treated with sham Ab or GD1a/GT1b-2b mAb (D). *p < 0.001 (Two-way ANOVA, Tukey’s multiple comparisons test). N  =  12 per group. Error bars, s.e.m. Scale bar, 10 µm. WT  =  wild type; NS  =  not significant; MF  =  myelinated nerve fibers.
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pone-0088703-g007: Anti-glycan Ab-mediated inhibition of axon regeneration was independent of activating FcγRIV.Sciatic nerve micrographs from Fcgr4- mice treated with sham Ab or GD1a/GT1b-2b mAb (A). MF counts in sciatic (B) or tibial (C) nerves from WT or Fcgr4- mice treated with sham Ab or GD1a/GT1b-2b mAb. Quantitative electrophysiological data showing CMAP amplitudes of WT or Fcgr4- mice treated with sham Ab or GD1a/GT1b-2b mAb (D). *p < 0.001 (Two-way ANOVA, Tukey’s multiple comparisons test). N  =  12 per group. Error bars, s.e.m. Scale bar, 10 µm. WT  =  wild type; NS  =  not significant; MF  =  myelinated nerve fibers.

Mentions: Our results showed that Fcer1α- and Fcgr4- mice were susceptible to anti-glycan Ab-mediated inhibition of axon regeneration (Figures. 6 and 7), whereas this inhibitory effect was almost completely reversed in Fcgr3- mice (Figure 8). We found that anti-glycan Ab-mediated inhibition of axon regeneration was independent of activating FcγRI. The morphological data showed that the treatment with GD1a/GT1b-2b significantly reduced the numbers of regenerating MF in sciatic (298±35) and tibial (34±14) nerves in Fcer1α- mice compared with sham Ab treatment (2197±93 at sciatic and 542±80 at tibial nerve levels) (Figures 6A-6C). There was no significant difference in anti-glycan Ab induced inhibition of axon regeneration between Fcer1α- mice (SN, 298±35 and TN, 34±14) and WT control animals (SN, 286±39 and TN, 25±3). Electrophysiological studies were consistent with morphological findings showing that the treatment with GD1a/GT1b-2b mAb abolished evoked CMAP responses in Fcer1α- mutants (Figure 6D). Next, our studies indicated that anti-glycan Ab-mediated inhibition of axon regeneration was also independent of activating FcγRIV. We found that there was a significant decrease in numbers of regenerating MF in GD1a/GT1b-2b-treated sciatic (282±82) and tibial (15±3) nerves in Fcgr4- mice compared with sham Ab treated sciatic (2952±64) and tibial (795±68) nerves (Figures 7A-7C). The anti-glycan Ab mediated inhibition of axon regeneration was similar between Fcgr4- mice (SN, 282±82 and TN, 15±3) and their littermate control animals (SN, 320±50 and TN, 21±2). Electrophysiological studies were consistent with morphometry showing that the treatment with GD1a/GT1b-2b mAb abolished evoked CMAP responses in Fcgr4- mutants (Figure 7D).


Fcγ receptor-mediated inflammation inhibits axon regeneration.

Zhang G, Bogdanova N, Gao T, Song JJ, Cragg MS, Glennie MJ, Sheikh KA - PLoS ONE (2014)

Anti-glycan Ab-mediated inhibition of axon regeneration was independent of activating FcγRIV.Sciatic nerve micrographs from Fcgr4- mice treated with sham Ab or GD1a/GT1b-2b mAb (A). MF counts in sciatic (B) or tibial (C) nerves from WT or Fcgr4- mice treated with sham Ab or GD1a/GT1b-2b mAb. Quantitative electrophysiological data showing CMAP amplitudes of WT or Fcgr4- mice treated with sham Ab or GD1a/GT1b-2b mAb (D). *p < 0.001 (Two-way ANOVA, Tukey’s multiple comparisons test). N  =  12 per group. Error bars, s.e.m. Scale bar, 10 µm. WT  =  wild type; NS  =  not significant; MF  =  myelinated nerve fibers.
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pone-0088703-g007: Anti-glycan Ab-mediated inhibition of axon regeneration was independent of activating FcγRIV.Sciatic nerve micrographs from Fcgr4- mice treated with sham Ab or GD1a/GT1b-2b mAb (A). MF counts in sciatic (B) or tibial (C) nerves from WT or Fcgr4- mice treated with sham Ab or GD1a/GT1b-2b mAb. Quantitative electrophysiological data showing CMAP amplitudes of WT or Fcgr4- mice treated with sham Ab or GD1a/GT1b-2b mAb (D). *p < 0.001 (Two-way ANOVA, Tukey’s multiple comparisons test). N  =  12 per group. Error bars, s.e.m. Scale bar, 10 µm. WT  =  wild type; NS  =  not significant; MF  =  myelinated nerve fibers.
Mentions: Our results showed that Fcer1α- and Fcgr4- mice were susceptible to anti-glycan Ab-mediated inhibition of axon regeneration (Figures. 6 and 7), whereas this inhibitory effect was almost completely reversed in Fcgr3- mice (Figure 8). We found that anti-glycan Ab-mediated inhibition of axon regeneration was independent of activating FcγRI. The morphological data showed that the treatment with GD1a/GT1b-2b significantly reduced the numbers of regenerating MF in sciatic (298±35) and tibial (34±14) nerves in Fcer1α- mice compared with sham Ab treatment (2197±93 at sciatic and 542±80 at tibial nerve levels) (Figures 6A-6C). There was no significant difference in anti-glycan Ab induced inhibition of axon regeneration between Fcer1α- mice (SN, 298±35 and TN, 34±14) and WT control animals (SN, 286±39 and TN, 25±3). Electrophysiological studies were consistent with morphological findings showing that the treatment with GD1a/GT1b-2b mAb abolished evoked CMAP responses in Fcer1α- mutants (Figure 6D). Next, our studies indicated that anti-glycan Ab-mediated inhibition of axon regeneration was also independent of activating FcγRIV. We found that there was a significant decrease in numbers of regenerating MF in GD1a/GT1b-2b-treated sciatic (282±82) and tibial (15±3) nerves in Fcgr4- mice compared with sham Ab treated sciatic (2952±64) and tibial (795±68) nerves (Figures 7A-7C). The anti-glycan Ab mediated inhibition of axon regeneration was similar between Fcgr4- mice (SN, 282±82 and TN, 15±3) and their littermate control animals (SN, 320±50 and TN, 21±2). Electrophysiological studies were consistent with morphometry showing that the treatment with GD1a/GT1b-2b mAb abolished evoked CMAP responses in Fcgr4- mutants (Figure 7D).

Bottom Line: Anti-glycan/ganglioside antibodies are the most common immune effectors found in patients with Guillain-Barré Syndrome, which is a peripheral autoimmune neuropathy.These findings have clinical implications for nerve repair and recovery in antibody-mediated immune neuropathies.Our results add to the complexity of axon regeneration in injured peripheral and central nervous systems as adverse effects of B cells and autoantibodies on neural injury and repair are increasingly recognized.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Texas Medical School at Houston, Houston, Texas, United States of America.

ABSTRACT
Anti-glycan/ganglioside antibodies are the most common immune effectors found in patients with Guillain-Barré Syndrome, which is a peripheral autoimmune neuropathy. We previously reported that disease-relevant anti-glycan autoantibodies inhibited axon regeneration, which echo the clinical association of these antibodies and poor recovery in Guillain-Barré Syndrome. However, the specific molecular and cellular elements involved in this antibody-mediated inhibition of axon regeneration are not previously defined. This study examined the role of Fcγ receptors and macrophages in the antibody-mediated inhibition of axon regeneration. A well characterized antibody passive transfer sciatic nerve crush and transplant models were used to study the anti-ganglioside antibody-mediated inhibition of axon regeneration in wild type and various mutant and transgenic mice with altered expression of specific Fcγ receptors and macrophage/microglia populations. Outcome measures included behavior, electrophysiology, morphometry, immunocytochemistry, quantitative real-time PCR, and western blotting. We demonstrate that the presence of autoantibodies, directed against neuronal/axonal cell surface gangliosides, in the injured mammalian peripheral nerves switch the proregenerative inflammatory environment to growth inhibitory milieu by engaging specific activating Fcγ receptors on recruited monocyte-derived macrophages to cause severe inhibition of axon regeneration. Our data demonstrate that the antibody orchestrated Fcγ receptor-mediated switch in inflammation is one mechanism underlying inhibition of axon regeneration. These findings have clinical implications for nerve repair and recovery in antibody-mediated immune neuropathies. Our results add to the complexity of axon regeneration in injured peripheral and central nervous systems as adverse effects of B cells and autoantibodies on neural injury and repair are increasingly recognized.

Show MeSH
Related in: MedlinePlus