A derivative of the plasma protease inhibitor α2‐macroglobulin regulates the response to peripheral nerve injury

Abstract

Peripheral nerve injury induces endoneural inflammation, controlled by diverse cytokines and extracellular mediators. Although inflammation is coupled to axonal regeneration, fulminant inflammation may increase nerve damage and neuropathic pain. α₂‐Macroglobulin (α2M) is a plasma protease inhibitor, cytokine carrier, and ligand for cell‐signaling receptors, which exists in two well‐characterized conformations and in less well‐characterized intermediate states. Previously, we generated an α2M derivative (α₂‐macroglobulin activated for cytokine binding; MAC) similar in structure to α₂M conformational intermediates, which binds tumor necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β), and inhibits endotoxin toxicity. In this study, we report that the continuum of cytokines that bind to MAC includes IL‐6 and IL‐18. MAC inhibited TNF‐α‐induced p38 mitogen‐activated protein kinase activation and cell death in cultured Schwann cells. When administered by i.p. injection to mice with sciatic nerve crush injury, MAC decreased inflammation and preserved axons. Macrophage infiltration and TNF‐α expression also are decreased. MAC inhibited TNF‐α expression in the chronic constriction injury model of nerve injury. When MAC was prepared using a mutated recombinant α2M, which does not bind to the α2M receptor, low‐density lipoprotein receptor‐related protein‐1, activity in the chronic constriction injury model was blocked. These studies demonstrate that an α2M derivative is capable of regulating the response to peripheral nerve injury by a mechanism that requires low‐density lipoprotein receptor‐related protein‐1.