Induction of neuropeptide gene expression and blockade of retrograde transport in facial motor neurons following local peripheral nerve inflammation in severe combined immunodeficiency and BALB/C mice

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Abstract

Peripheral nerve inflammation is a common clinical problem that accompanies nerve injury and several diseases including Guillain-Barré syndrome and acute and chronic inflammatory demyelinating polyneuropathy. To determine if neuropeptides are induced in motor neurons after inflammation and to study the mechanisms involved, a nerve cuff soaked in complete Freund's adjuvant (CFA) was applied locally to the facial nerve of Balb/C mice. This procedure resulted in an influx of lymphocytes and macrophages to the affected area and a blockade of retrograde axonal transport distal, but not proximal, to the site of application. The same treatment resulted in a strong ipsilateral induction of pituitary adenylyl cyclase activating peptide (PACAP) gene expression in motor neurons in the facial motor nucleus. Because the changes could have occurred due to the loss of target-derived factors or to the production of new factors by immune cells, we studied the effect of the inflammatory stimulus on PACAP mRNA in mice with severe combined immunodeficiency (SCID). As expected, SCID mice showed a severely reduced influx of T-lymphocytes but not macrophages to the peripheral nerve. Moreover, although retrograde transport distal to the inflammation site was blocked similarly in control and SCID mice, the number of motor neurons expressing PACAP mRNA after CFA application was significantly reduced in SCID mice. The data indicate that the induction of PACAP mRNA during nerve inflammation requires the involvement of lymphocytes. However, because the induction of PACAP gene expression was only partially blocked in SCID mice, macrophages, loss of target-derived factors, or other mechanisms may also contribute to the upregulation of PACAP gene expression in motor neurons after nerve inflammation.

Section snippets

Animals and surgery

Mice used included SCID mice (C.B-17 mutation [Prkdc]), maintained at the University of California at Los Angeles on a Balb/C background), and Balb/C controls.Animals were treated in accordance with the UCLA animal research committee and international guidelines on the ethical treatment of animals. Care was taken so that the number of animals used and their suffering was minimized. Mice were housed in a temperature-controlled vivarium with 12-h light/dark cycle and access to food and water ad

Results

Previous studies showed that axotomy of the facial nerve resulted in a strong upregulation of PACAP mRNA in the FMN 4 days after axotomy (Armstrong et al., 2003). To determine if this changes might have been due to inflammatory mediators produced at the injury site, we performed experiments in which we applied an inflammatory stimulus locally to the facial nerve (in the form of a nerve cuff soaked in CFA). This procedure was found to result in a significant influx of lymphocytes and macrophages

Discussion

Significant increases and decreases in neuropeptide expression have been demonstrated in several nerve injury models, but the factors responsible for these changes have not been identified or inferred, except in a few cases (Zigmond, 1997; Jongsma-Wallin et al., 2001, 2003). We previously found that PACAP, VIP, and galanin expression is upregulated following facial nerve axotomy and that the effect on PACAP is specifically blocked in SCID mice. This result suggests that lymphocyte-released

Acknowledgments

This work was supported by NIH grants HD06576 and HD04612, and grants from the Norman Cousins Center for Psychoneuroimmunology, and the Roman Reed Spinal Cord Injury Research Fund of California. Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center and Center for AIDS Research Flow Cytometry Core Facility that is supported by National Institutes of Health awards CA-16042 and AI-28697, by the Jonsson Cancer Center, the UCLA AIDS Institute, and the UCLA Geffen School of

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