TLR and NOD2 ligands induce cell proliferation in the rat intact spinal cord.
We demonstrate, by 5-bromo-2'-deoxyuridine (BrdU) tracing, the effects of peripheral administration of toll-like receptor (TLR) and NOD2 ligands (stimulators of the innate immune system) on the proliferation of spinal cord cells. Bolus injection of phosphorothioate oligonucleotides containing CpG motifs had no prominent effects on spinal cord neural progenitor cell proliferation, whereas single intraperitoneal injection of polyinosine-polycytidylic acid (Poly I:C, TLR3 ligand), lipopolysaccharide (LPS, TLR4 ligand), R848 (TLR7/8 ligand), or N-acetylmuramyldipeptide (MDP, Nod2 ligand) temporarily increased the number of BrdU(+) cells in the spinal cord. For Poly I:C- or R848-treated groups, the density of BrdU cells reached maximal levels on days 2 to 3 postinjection and then rapidly declined to baseline levels. Only a few of the proliferating cells were of microglial origin, but BrdU(+)/nestin(+) cells were found, suggestive of a proliferation of local progenitor cells. In addition, stimulation of cell proliferation correlated with activation of the innate immune system, that is, microglial cells. Interestingly, activation and cell proliferation was inhibited by corticosteroid dexamethasone but not by indomethacin. These findings suggest an intricate interaction of phylogenetically ancient cellular processes of the innate immune system and regeneration.
Su
Yanhua
Y
Institute of Brain Research, University of Tuebingen, Germany.
Zhang
Zhiren
Z
Trautmann
Katrin
K
Xu
Shunqing
S
Schluesener
Hermann J
HJ
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D053331:Ectodysplasins; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D007381:Intermediate Filament Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D053473:Nod2 Signaling Adaptor Protein; D011070:Poly I-C / Q000494:pharmacology; D011107:Polylysine / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013116:Spinal Cord / Q000166:cytology*; D051193:Toll-Like Receptors / Q000502:physiology*; D048069:Tumor Necrosis Factors / Q000378:metabolism
D053331:Ectodysplasins; C506019:Eda protein, mouse; D007093:Imidazoles; D007381:Intermediate Filament Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; C577486:Nes protein, rat; D064231:Nestin; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D051193:Toll-Like Receptors; D048069:Tumor Necrosis Factors; D011107:Polylysine; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C040125:poly ICL; D001973:Bromodeoxyuridine; D011070:Poly I-C; C402365:resiquimod