Schwann cells promote post-traumatic nerve inflammation and neuropathic pain through MHC class II

Maike Hartlehnert,Tim Hagenacker,David Kindermann,Maria Schäfers,Bernd C Kieseier,Angelika Derksen,Gerd Meyer Zu Horste,Mathias Pawlak

doi:10.1038/s41598-017-12744-2

Abstract

The activation of T helper cells requires antigens to be exposed on the surface of antigen presenting cells (APCs) via MHC class II (MHC-II) molecules. Expression of MHC-II is generally limited to professional APCs, but other cell types can express MHC-II under inflammatory conditions. However, the importance of these conditional APCs is unknown. We and others have previously shown that Schwann cells are potentially conditional APCs, but the functional relevance of MHC-II expression by Schwann cells has not been studied in vivo. Here, we conditionally deleted the MHC-II β-chain from myelinating Schwann cells in mice and investigated how this influenced post-traumatic intraneural inflammation and neuropathic pain using the chronic constriction injury (CCI) model. We demonstrate that deletion of MHC-II in myelinating Schwann cells reduces thermal hyperalgesia and, to a lesser extent, also diminishes mechanical allodynia in CCI in female mice. This was accompanied by a reduction of intraneural CD4+ T cells and greater preservation of preferentially large-caliber axons. Activation of T helper cells by MHC-II on Schwann cells thus promotes post-traumatic axonal loss and neuropathic pain. Hence, we provide experimental evidence that Schwann cells gain antigen-presenting function in vivo and modulate local immune responses and diseases in the peripheral nerves.

Highlights

A central element of all adaptive immune responses is recognition of antigens by T cells
We found that Schwann cell–restricted MHC class II (MHC-II) deficiency in female P0CreIAbfl/fl mice did not alter the proportion of myelinated axons (Fig. 2a) or alter the myelin thickness quantified by g ratio measurements distal to the site of injury (Fig. 2b; p-value = 0.4809)
We found that the threshold for paw withdrawal to heat was significantly higher in female P0CreIAbfl/fl mice than in female IAbfl/fl mice using both absolute (Fig. 4a, p-value = 0.0065) and relative quantification (Fig. 4b, p-value = 0.0202), indicating that deleting MHC-II from peripheral myelination Schwann cells led to a decreased sensitivity to noxious thermal stimuli and decreased thermal hyperalgesia

Summary

Introduction

A central element of all adaptive immune responses is recognition of antigens by T cells. We and others have previously shown that the myelin-forming glial cells of the peripheral nervous system (PNS) - named Schwann cells - can gain MHC-II expression after traumatic[8] and inflammatory injury[9] and may present antigens in vitro[10,11] These surprising findings suggest a previously unappreciated function of Schwann cells as conditional APCs9 in addition to their function in myelination and axonal support[12]. The ability of Schwann cells to present antigens promotes post-traumatic neuropathic pain With these observations, we provide strong experimental evidence that Schwann cells can function as conditional APCs and - in a more general context - our data support the conditional APC paradigm in a living organism

Methods

Results

Conclusion