High or low density of sympathetic nerve fibers in inflammatory lesions: Comment on the article by Ghilardi et al
Article first published online: 27 OCT 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 11, pages 3823–3825, November 2012
How to Cite
Straub, R. H. (2012), High or low density of sympathetic nerve fibers in inflammatory lesions: Comment on the article by Ghilardi et al. Arthritis & Rheumatism, 64: 3823–3825. doi: 10.1002/art.34623
- Issue published online: 27 OCT 2012
- Article first published online: 27 OCT 2012
- Accepted manuscript online: 17 JUL 2012 12:49PM EST
To the Editor:
Duo cum faciunt idem, non est idem can be translated to “when two do the same, it isn't the same.” This quotation from Adelphoe by the Roman playwright Terence is well suited to describe the discrepancies between results found in a recent study by Ghilardi and colleagues (1) and those found by others (2–5). In inflamed tissue, Ghilardi et al found high sympathetic nerve fiber density, while other groups found low sympathetic nerve fiber density.
Ghilardi et al investigated innervation of synovial tissue from knee joints of young adult mice 28 days after intraarticular injection of Freund's complete adjuvant (CFA), which is known to elicit a typical inflammatory pain response (1). No adaptive immune response is expected in this model of a chronic inflammatory condition. Along with an increased density of CD31+ vessels and CD68+ macrophages, they found an increased density of calcitonin gene-related peptide–positive nerve fibers (sensory) and tyrosine hydroxylase–positive sympathetic nerve fibers (1).
Sprouting of nerve fibers was described in the 19th century as a general phenomenon of nerve fiber repair (6). Furthermore, it was linked to the phenomenon of peripheral sensitization of painful stimuli and neurogenic inflammation (7). In Ghilardi and colleagues' study, tissue sections were scanned at low power to identify areas with the highest capillary or nerve fiber density in the synovium. These areas were called hot spots, and there were many of them adjacent to the meniscus (1). In the hot spots, densities of sensory and sympathetic nerve fibers were increased in CFA-injected animals as compared to those in control animals, in which the synovial–meniscal interface was used to study a comparable region.
In studies of human and rodent innervation of inflamed tissue performed by my research group, we counted the number of nerve fibers per high-power field expressed as number/mm2 and did not focus on hot spots. In addition, we usually did not examine the meniscus. Sometimes, we also found hot spots in the proximity of newly formed vascular networks, but, in contrast to our usual practice of counting nerve fibers in inflamed tissue, we omitted counting nerve fibers in these areas (4, 5). We ignored these areas because counting the number of nerve fibers per high-power field in a hot spot was impossible (exact separation of fibers was not possible). Ghilardi et al used a different technique, meticulously measuring nerve fiber length in a given tissue volume, where nerve fibers were manually traced and density was expressed as mm/mm3 (1). Thus, with their technique, the density per volume in a hot spot near the meniscus is ascertained, while our work ascertained the average density per area outside hot spots in the entire synovium. Figure 1 summarizes these findings.
The role of hot spots is presently not known. While nerve growth factor seems to be an important stimulus of hot spot generation (1), we reasoned that specific nerve-repellent factors of sympathetic nerve fibers are responsible for overall lower synovial tissue density under inflammatory conditions (8, 9). A recent study introduced interleukin-17A as a possible factor in the growth of sympathetic nerve fibers, but the authors of that article did not study tissue innervation, and the discussion is unbalanced (10). Ghilardi et al interpreted sympathetic hot spots as a possible causal factor in adrenergically supported pain. However, whether hot spots perform this function remains in question.
Noradrenaline has a higher affinity for α-adrenoceptors (∼10−8M) as compared to β-adrenoceptors (∼10−6M) (11). It has been reported that noradrenaline concentrations in the proximity of nerve terminals can be as high as 10−5M (12). Thus, in hot spots concentrations that are relevant for β-adrenoceptor binding would be expected (Figure 1). Since mainly α-adrenergic signaling was linked to peripheral sensitization of sensory nerve fiber endings in sympathetic-sensory coupling (13), concentrations of noradrenaline might be too high for sensory nerve fiber sensitization in hot spots. Thus, α-adrenergic signaling outside hot spots and β-adrenergic signaling inside hot spots would be expected (Figure 1).
It can be hypothesized that hot spots might be zones of little proinflammatory activity since β-adrenergic signaling has many antiinflammatory effects on innate and adaptive immune cells. The finding of a higher density of CD68+ macrophages in these zones (1) does not contradict this hypothesis, because this type of macrophage can be an alternatively activated M2-type macrophage.
Although the study by Ghilardi and colleagues provides important new ideas for understanding sympathetic tissue innervation under normal conditions and inflammation, a more balanced discussion would have been desirable.
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Rainer H. Straub MD, PhD*, * University Hospital Regensburg, Regensburg, Germany.