A derivative of the plasma protease inhibitor 72-macroglobulin regulates the response to peripheral nerve injury

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. alpha 2-Macroglobulin (alpha 2M) 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 alpha 2M derivative (alpha 2-macroglobulin activated for cytokine binding; MAC) similar in structure to OF2M conformational intermediates, which binds tumor necrosis factor-a (TNF-alpha) and interleukin-1 beta (IL-1 beta), and inhibits enclotoxin toxicity. In this study, we report that the continuum of cytokines that bind to MAC includes IL-6 and IL-18. MAC inhibited TNF-alpha-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 TINIF-alpha expression also are decreased. MAC inhibited TNF-alpha expression in the chronic constriction injury model of nerve injury. When MAC was prepared using a mutated recombinant alpha 2M, which does not bind to the alpha 2M receptor, low-density lipoprotein receptor- related protein-1, activity in the chronic constriction injury model was blocked. These studies demonstrate that an alpha 2M derivative is capable of regulating the response to peripheral nerve injury by a mechanism that requires low-density lipoprotein receptorrelated protein-1.