A derivative of the plasma protease inhibitor alpha(2)-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 (alpha2M) 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 alpha2M derivative (alpha(2)-macroglobulin activated for cytokine binding; MAC) similar in structure to alpha(2)M conformational intermediates, which binds tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), 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-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 TNF-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 alpha2M, which does not bind to the alpha2M receptor, low-density lipoprotein receptor-related protein-1, activity in the chronic constriction injury model was blocked. These studies demonstrate that an alpha2M derivative is capable of regulating the response to peripheral nerve injury by a mechanism that requires low-density lipoprotein receptor-related protein-1.
Arandjelovic
Sanja
S
Department of Pathology, University of California, San Diego School of Medicine, La Jolla, California 92093, USA.
Dragojlovic
Nikola
N
Li
Xiaoqing
X
Myers
Robert R
RR
Campana
W Marie
WM
Gonias
Steven L
SL
D000818:Animals; D001369:Axons / Q000502:physiology; D016923:Cell Death; D002478:Cells, Cultured; D003251:Constriction, Pathologic / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009409:Nerve Crush; D059348:Peripheral Nerve Injuries; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012583:Schwann Cells / Q000187:drug effects; D012584:Sciatic Nerve / Q000293:injuries; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology; D000511:alpha-Macroglobulins / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000511:alpha-Macroglobulins; D048051:p38 Mitogen-Activated Protein Kinases