Abstract
One of the changes brought about by Wallerian degeneration distal to nerve injury is disintegration of axonal mitochondria and consequent leakage of mitochondrial DNA (mtDNA)—the natural ligand for the toll-like receptor 9 (TLR9). RT-PCR and immunohistochemical or Western blot analyses were used to detect TLR9 mRNA and protein respectively in the lumbar (L4-L5) and cervical (C7-C8) dorsal root ganglia (DRG) ipsilateral and contralateral to a sterile unilateral sciatic nerve compression or transection. The unilateral sciatic nerve lesions led to bilateral increases in levels of both TLR9 mRNA and protein not only in the lumbar but also in the remote cervical DRG compared with naive or sham-operated controls. This upregulation of TLR9 was linked to activation of the Nuclear Factor kappa B (NFκB) and nuclear translocation of the Signal Transducer and Activator of Transcription 3 (STAT3), implying innate neuronal immune reaction and a pro-regenerative state in uninjured primary sensory neurons of the cervical DRG. The relationship of TLR9 to the induction of a pro-regenerative state in the cervical DRG neurons was confirmed by the shorter lengths of regenerated axons distal to ulnar nerve crush following a previous sciatic nerve lesion and intrathecal chloroquine injection compared with control rats. The results suggest that a systemic innate immune reaction not only triggers the regenerative state of axotomized DRG neurons but also induces a pro-regenerative state further along the neural axis after unilateral nerve injury.
Highlights
The primary sensory neurons of dorsal root ganglia (DRG) sendoff afferent axons, whose peripheral branches extend through peripheral nerves to the target tissue
Wallerian degeneration distal to nerve injury releases a large spectrum of DAMPs produced by cleavage of the endoneurial extracellular matrix and disintegration of axonal plasma membrane and mitochondria [8,20]
The mitochondrial DNA (mtDNA) produced by Wallerian degeneration (WD), as in any other tissue injury, can be released into the bloodstream and induce inflammatory reactions in tissue remote from the site of primary trauma [21]. mtDNA get into the bloodstream because the blood–nerve barrier is interrupted in distal segments of the injured nerve [22]
Summary
The primary sensory neurons of dorsal root ganglia (DRG) sendoff afferent axons, whose peripheral branches extend through peripheral nerves to the target tissue. Injury to peripheral axonal branches induces transcription-dependent changes of regeneration-associated genes and proteins, enhancing the regeneration potential of DRG neurons and promoting regeneration of the damaged axons [1,2]. This conditioning lesion of peripheral axons allows regeneration of central axonal branches, but prior injury to these branches is insufficient to activate the same neuronal regeneration program [3,4,5]. Wallerian degeneration (WD) is a cascade of cellular and molecular events distal to a nerve injury that releases a large spectrum of molecules originating from the disintegration of axons and their myelin sheaths and the extracellular matrix of the endoneurium [6,7,8,9]
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