Fcγ Receptor-Mediated Inflammation Inhibits Axon Regeneration

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.

Role of Fcγ Receptor Mediated Inflammation in Immune Neuropathies

“…These studies provide further experimental evidence of the role of macrophages and activating FcγRs mediated-inflammation in Ab-mediated experimental models of autoimmune neuropathies. In line with these animal studies, we also found that macrophages and Schwann cells do express FcγR common chain in the nerves of patients with axonal GBS [43]. The FcγR common chain expression was significantly upregulated in GBS nerves compared to controls and activated macrophages expressing activating FcγRs were found adjacent to widened nodes in axonal GBS patient nerves (Figure 1).…”

“…Our studies in op/op mice confirmed the involvement of macrophages in AGA-mediated pathological effects in this model [43]. In order to dissect the contribution of FcγRs-bearing circulating macrophage and FcγRs-expressing resident endoneurial glial cells, a nerve grafting study, in which wild type (WT) or activating FcγRs-null (Fcer1g-/-) nerve segments (donors) were transplanted in background matched WT or Fcer1g-/-(hosts) mice, was carried out [43]. We found that there is significantly more axon regeneration in WT or FcγRs-null grafts implanted in FcγRs-null hosts, compared to WT or FcγRs-null grafts implanted in WT hosts.…”

“…We showed that passive transfer of AGAs (experimental and human) impair nerve repair and severely inhibit axon regeneration, and ICs formed by AGA and its target antigen is required for the inhibition in nerve crush model [19,42,43]. These experimental findings echo the clinical association of AGAs and poor recovery in GBS.…”

Development and Characterization of Monoclonal Antibodies Specific for Mouse and Human Fcγ Receptors

“…This observation may therefore relate to the potent immune stimulating activity of mAb targeting TNF receptor super family members such as CD40 and DR4/5 (12)(13)(14)50). In contrast to direct targeting mAb such as rituximab, which are impaired by mFcgRII and hFcgRIIB, these receptors are now known to be an important component of immunomodulatory mAb activity, where they serve to further cross-link the target receptor for optimal signaling (20)(21)(22)(23)(24)(25)reviewed in Ref. 26).…”

“…Heterozygous mFcgRIV +/2 mice, from the European Conditional Mouse Mutagenesis Program consortia distributed by the Helmholtz Zentrum M€ unchen (Munich, Germany), have been described previously (23) and were intercrossed to obtain mFcgRIV 2/2 . All strains were backcrossed onto the BALB/c or C57BL/6J background for at least 10 generations.…”