Schwann cell-secreted frizzled-related protein 1 dictates neuroinflammation and peripheral nerve degeneration after neurotrauma

Abstract

Neurotrauma in limbs can induce sustained neuroinflammation, resulting in persistent disruption of nerve tissue architecture and retardation of axon regrowth. Despite macrophage-mediated inflammation promoting the removal of necrotic neural components and stimulating neo-vessel ingrowth, detrimental shifts in macrophage phenotype exacerbate nerve degeneration. Herein, we find that peripheral nerve injuries (PNIs) result in abundant secreted frizzled-related protein 1 (sFRP1) expression, particularly by Schwann cells (SCs). Heat shock protein 90 (HSP90) in macrophages recognizes sFRP1 and triggers a dysregulated secretion of inflammatory mediators. Single-cell atlas of human injured peripheral nerves reveals the appearance of sFRP1-expressing SCs with mesenchymal traits and macrophages with a proinflammatory genetic profile. Deletion of either SC-specific sFRP1 or macrophage-specific HSP90 alleviates neuroinflammation and prevents the progression of nerve degeneration. Together, our findings implicate the response of macrophages to SC-derived sFRP1 in exacerbating nerve damage following PNIs. • Upon PNIs, abundant levels of sFRP1 are released into the nerve ECM by SCs • sFRP1 deletion alleviates immune insults and prevents axon degeneration • HSP90 binds to sFRP1 in macrophages to mediate neuroinflammation • Blocking sFRP1-HSP90 signaling with neutralizing antibody improves nerve repair Neurotrauma in limbs can induce sustained neuroinflammation, resulting in the retardation of axon regrowth. Here, Yao et al. reveal that Schwann cell-derived sFRP1 binds to HSP90 in macrophages, thus triggering a dysregulated secretion of inflammatory mediators. Functional blockade of sFRP1 signaling improves nerve repair.