Sciatic injury upregulates NGF and mast cells in the skin: Montalcini explains a 2012 paper


mast cells PEA and NGF

Levi-Montalcini in mast cells and NGF, and sciatic pain

mast cell and Montalcini

rita-mast cells 3

mast cells after sciatic injury

Hypothesis NGF and mast cell in sciatic pain

Mast cells and NGF: conlusion by Montalcini

Copyright.svgCopyright on all cartoons by the Chronic Pain Coalition, JMKHLOGO

Paper discussed by Montalcini: Neurotrophic factor changes in the rat thick skin
following chronic constriction injury of the sciatic nerve, by Jennifer C Peleshok and Alfredo Ribeiro-da-Silva; Molecular Pain 2012, 8:1

Conclusion section on mast cells and sciatic pain

In summary, we were able to show that following application of the traditional CCI model of neuropathic pain, mast cells followed by keratinocytes and vascular endothelium upregulate proNGF, and that this upregula- tion was significant until at least four weeks post-injury, as confirmed by Western blotting. This is in contrast to the relative changes in TrkA protein levels and p75 within the same area. Following nerve injury, there was a dying back of peptidergic afferents and a correlative decrease in TrkA protein until four weeks post-injury, at which point it returned to levels of sham-operated animals, coinciding with the recovery of the peptidergic innervation. Our data suggests that the sprouting after lesion of NGF-responsive fibers is initiated by the increase in local proNGF (and thus mNGF) levels, and may be maintained with the involvement of other factors.

AND in the discussion of their data:

In this study, we performed for the first time a detailed description of the relationship of the NGF-responsive nerve fiber populations to the neurotrophin-producing cells following the application of a commonly used neuropathic pain model, the CCI of the sciatic nerve. Because NGF is known to occur in cells in its precursor form [34], proNGF, we used antibodies specific for this precursor form.
Previous research has focused on the changes in mature NGF uptake following nerve injury given that mNGF is expressed at very low levels in target tissues in sham or naïve animals [36]. Methods such as in situ hybridization have shown that the mRNA for NGF is transcribed in Schwann cells [24,45] and fibroblasts [60] and that the protein exists in mast cells [26] and kerati- nocytes [27]. Cultured mast cells have also been demon- strated to upregulate NGF when presented with the cytokines IL-1b and TNF-a [39,40,61], and when degranulated release NGF into the culture media [26]. Schwann cell production of NGF has been demonstrated using culturing methods in which morphology of Schwann cells in explanted optic nerve has been shown to correlate with NGF expression [45]. A line of evi- dence that has pervaded research literature is that a che- moattractant gradient of NGF created by its retention through cell surface expressed low-affinity NGF recep- tors, p75 [53,62]. However, due to the restrictions of the available methodology, this has not yet been directly proven.
In the current study we provide some important new evidence, namely that a significant expression of proNGF by Schwann cells, identified by S100 immunor- eactivity, was not evident. We also show an association of proNGF-producing cell types with NGF-responsive sensory and sympathetic fibers. Consistent with a num- ber of prior observations, we were able to confirm the observed upregulation of p75 on non-neuronal cell types, namely Schwann cells, following nerve injury [16,23,63]. This upregulation was significant from early time points.

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