ABSTRACT
We have previously demonstrated that one of the peripheral nerve responses to injury is the overexpression of hemopexin (HPX). Here, we demonstrate that Wallerian degeneration is required for this response, since HPX does not increase in C57BL/Wlds mice, which display a severely impaired Wallerian degeneration. We also show that HPX synthesis is dramatically increased in macrophages during their activation or after IL-6 stimulation. However, IL-6-driven HPX overexpression occurs in vivo and in vitro in the absence of substantial macrophage invasion. We conclude that, after nerve injury, HPX overexpression occurs first in Schwann cells as a result of axotomy and is subsequently regulated by inflammation. Furthermore, our results and those already described suggest that IL-6, synthesized by the various cell types producing HPX, control nerve HPX expression via paracrine and autocrine mechanisms.
Subject(s)
Axons/physiology , Hemopexin/metabolism , Neuritis/physiopathology , Peripheral Nerves/metabolism , Peripheral Nervous System Diseases/physiopathology , Animals , Axons/ultrastructure , Cells, Cultured , Lipopolysaccharides/pharmacology , Lysophosphatidylcholines/pharmacology , Macrophages/metabolism , Mice , Mice, Inbred C57BL/genetics , Mice, Mutant Strains , Neuritis/metabolism , Neuritis/pathology , Optic Nerve Injuries/metabolism , Peripheral Nervous System Diseases/metabolism , Peripheral Nervous System Diseases/pathology , Rats , Rats, Sprague-Dawley , Sciatic Nerve/injuries , Sciatic Nerve/metabolism , Tissue Distribution , Wallerian Degeneration/pathology , Wallerian Degeneration/physiopathologyABSTRACT
In injured peripheral nerves, hemopexin mRNA is expressed by fibroblasts, Schwann cells, and invading blood macrophages, and the protein accumulates in the extracellular matrix. This and its absence of regulation in injured central optic nerve suggest that hemopexin could play a positive role in peripheral nerve repair. Here, we studied the regulation of hemopexin expression in degenerating and regenerating nerves. After a sciatic nerve injury, both the synthesis of hemopexin and the level of its mRNA increase sharply during the first 2 days, leading to an accumulation of hemopexin in the nerve. Afterward, hemopexin expression decreases progressively in regenerating nerves. In permanently degenerated nerves, it is again transiently increased and then strongly decreased, whereas hemopexin from blood origin is accumulating. As part of the elucidation of the complex regulation of hemopexin expression in injured nerves, we demonstrate that interleukin-6 increases hemopexin synthesis in intact nerves, whereas adult rat serum, but not purified hemopexin, inhibits it in degenerated nerves. Hemopexin, known as acute-phase protein, is therefore one of the molecules rapidly and specifically up-regulated in injured peripheral nerves. More generally, our findings suggest that the acute phase could be not only a systemic liver-specific response but also a reaction of injured tissues themselves.
Subject(s)
Hemopexin/genetics , Nerve Degeneration/metabolism , Nerve Regeneration/physiology , Sciatic Nerve/injuries , Sciatic Nerve/metabolism , Age Factors , Animals , Blood Proteins/pharmacology , Female , Gene Expression/drug effects , Gene Expression/physiology , Hemopexin/biosynthesis , Interleukin-6/pharmacology , Male , Nerve Regeneration/drug effects , RNA, Messenger/analysis , Rats , Rats, WistarABSTRACT
The recent demonstration of hemopexin synthesis in the adult rat sciatic nerve and its accumulation after injury has raised the question of the possible role of this acute phase protein during the process of nerve repair. To gain insight into its function, we have compared the distribution of both hemopexin and its messenger RNA in the peripheral and the central nervous systems. We find that hemopexin is present in all types of peripheral nerves and ganglia, confined to the extracellular matrix and basement membranes of the endoneurium, blood vessels and connective tissues. After injury, hemopexin messenger RNA is overexpressed by Schwann cells, fibroblasts and invading macrophages. The content in hemopexin protein increases in all nerves studied, without changes in localization. Therefore, hemopexin does not appear to be associated with the fate of myelin or with the regeneration of a particular type of nerve fibre. In the central nervous system, hemopexin messenger RNA cannot be detected and the protein is only found in basement membranes of the vascular system (capillaries, meninges and choroid plexus). Furthermore, hemopexin and its messenger RNA remain absent from the distal part of the injured optic nerves. Our results further support the idea that hemopexin plays specific roles during nerve repair, and that it may be associated with the endoneurial extracellular matrix.
