Fcγ receptor-mediated inflammation inhibits axon regeneration.

Gang Zhang,Martin J Glennie,Julia J Song,Kazim A Sheikh,Tong Gao,Nataliia Bogdanova,Mark S Cragg,Michael Costigan

doi:10.1371/journal.pone.0088703

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.

Highlights

Axon regeneration is a response of injured nerve cells that is critical for the restoration of structure and function after peripheral or central nervous systems injuries; a response that is key to recovery from numerous neurological disorders
Our results showed that GD1a/ GT1b-2b monoclonal antibodies (mAbs) induce significant inhibition of axon regeneration in WT and St8sia1-null animals but not in B4galnt1-null mice that did not express corresponding glycan antigens (Table 2), as reported previously [14]
Recruited macrophages are the major contributor to the Ab- and activating Fcc receptors (FccRs)-mediated inhibition of axon regeneration Our results showed that both endoneurial glia (Schwann and microglial cells) and recruited macrophages express activating FccRs (Figure 2D), we asked which FccRs-expressing cells participate in producing an inflammatory inhibitory milieu in the injured nerve

Summary

Introduction

Axon regeneration is a response of injured nerve cells that is critical for the restoration of structure and function after peripheral or central nervous systems injuries; a response that is key to recovery from numerous neurological disorders. Poor recovery in GBS and other neurological disorders commonly reflect failure of axon regeneration and reinnervation of targets. Studies indicate that anti-gangliosides Abs in GBS patients are induced via molecular mimicry [1,3]. Several studies have suggested that GBS patients with anti-GD1a and/or GM1 Abs are more likely to recover slowly and have poor prognosis [4,5,6,7,8,9,10,11,12,13]. Understanding the mechanisms underlying failure of axonal regeneration is of critical importance to devise strategies to enhance nerve repair and recovery in GBS and other immune neurological conditions

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Conclusion