TLR2 is required for the altered transcription of p75NGF receptors in gram positive infection.
Neuroimmune interactions play a decisive role in neuronal cell survival and cell death during neuronal injury, oxidative and free radical stress. In neurons, NGF occupancy of p75 neurotrophin receptor (p75(NTR)) has been shown to promote neuronal apoptosis, while occupancy of tropomyosin receptor kinase A (TrkA) promotes survival of injured neurons. In macrophages, recent results suggest that NGF via TrkA mediates resistance to cell death through the interaction with TLR2. We have investigated the transcriptional regulation of TrkA, p75(NTR) and their ligand nerve growth factor beta (NGFbeta) upon stimulation with the TLR2 ligand Staphylococcus aureus in the spleen of C57BL/6 mice, TLR2 (-/-) and p75(NTR) (-/-) mice. S. aureus challenge (i.p.) resulted in a significant increase in NGFbeta mRNA levels in C57BL/6 (100%), TLR2 (-/-) (300%) and p75(NTR) (-/-) mice (355%). TrkA mRNA levels were upregulated only in p75(NTR) (-/-) mice (87%) whereas in TLR2 (-/-) mice they remained unchanged and even decreased in C57BL/6 mice (46%). p75(NTR) mRNA was increased in spleen of C57BL/6 mice (60%) whereas the levels in TLR2 (-/-) mice remained almost unchanged. Finally, TLR2 mRNA was upregulated by 350% in C57BL/6 mice and by 283% in p75(NTR) (-/-) mice. These data suggest that in splenocytes signaling via TLR2 is required for Gram positive infection mediated alteration of neurotrophin receptor expression as observed in an in vivo infection model with transgenic mice. This observation provides a link between Gram-positive infection and neurotrophic responses, which may be important in preserving neurons at sites of the infection.
Wirz
Sebastian A
SA
The Harold L. Dorris Neurological Research Center, Department of Neuropharmacology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Tobias
Peter S
PS
Ulevitch
Richard J
RJ
Aribibe
Laurence
L
Bartfai
Tamas
T
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000235:genetics*; D013203:Staphylococcal Infections / Q000235:genetics / Q000382:microbiology / Q000503:physiopathology*; D013211:Staphylococcus aureus / Q000302:isolation & purification; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
D017931:DNA Primers; D009414:Nerve Growth Factors; D051195:Toll-Like Receptor 2