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Antigen-induced arthritis in rats is associated with increased growth-associated protein 43-positive intraepidermal nerve fibres remote from the joint.

Jochmann E, Boettger MK, Anand P, Schaible HG - Arthritis Res. Ther. (2015)

Bottom Line: However, paw skin and back skin revealed a significantly higher number of nerve fibres expressing GAP-43 at both the acute and chronic stages of AIA.Although the innervation of the skin remote from the joint did not show significant abnormalities of the other nerve fibre markers, the rapid and persistent increase of GAP-43 expression is conspicuous.The data suggest that immune-mediated arthritis is associated with changes in skin innervation remote from the inflamed joint, although the skin is not inflamed, which may contribute to symptoms in nonarticular tissue remote from the affected joint.

View Article: PubMed Central - PubMed

Affiliation: Institute of Physiology 1/Neurophysiology, Jena University Hospital, Friedrich Schiller University, Teichgraben 8, 07743, Jena, Germany. elisabeth.jochmann@med.uni-jena.de.

ABSTRACT

Introduction: Pain in arthritis may be experienced in regions outside the affected joint, and hyperalgesia may even be widespread. The spread of pain is usually attributed to mechanisms in the central nervous system. We investigated whether rats with antigen-induced arthritis (AIA) exhibit peripheral changes in skin innervation remote from the inflamed joint.

Methods: After immunization, unilateral AIA in the knee joint was induced in rats. Intraepidermal nerve fibre density was determined by immunohistochemical staining for protein gene product 9.5 (PGP 9.5) and for nerve fibres expressing calcitonin gene-related peptide (CGRP), substance P (SP), transient receptor potential vanilloid 1 (TRPV1; the heat and capsaicin receptor), β-tubulin, and growth-associated protein 43 (GAP-43; a marker of regenerating nerve fibres) in paw pad skin and back skin. Cluster of differentiation 11b (CD11b)-positive macrophages and CD3-positive T cells were quantified in skin, and macrophages were quantified in the lumbar dorsal root ganglia. In addition, pain-related behaviour was assessed.

Results: Intraepidermal nerve fibre density (PGP 9.5) and the numbers of fibres expressing CGRP, SP, TRPV1, or β-tubulin did not show a significant change in the acute (3 days) or chronic phase (21 days) of AIA compared with control rats that were only immunized. However, paw skin and back skin revealed a significantly higher number of nerve fibres expressing GAP-43 at both the acute and chronic stages of AIA. The skin of arthritic rats in these regions did not contain a greater density of CD11b and CD3 immune cells than the skin of control rats. Enhanced expression of GAP-43 in nerve fibres of the skin was not related to hyperalgesia in the joint, but it accompanied persistent secondary cutaneous hyperalgesia in the skin remote from the inflamed joint.

Conclusions: Although the innervation of the skin remote from the joint did not show significant abnormalities of the other nerve fibre markers, the rapid and persistent increase of GAP-43 expression is conspicuous. The data suggest that immune-mediated arthritis is associated with changes in skin innervation remote from the inflamed joint, although the skin is not inflamed, which may contribute to symptoms in nonarticular tissue remote from the affected joint.

No MeSH data available.


Related in: MedlinePlus

Anti-CD68 antibody (ED1) immunoreactivity in lumbar dorsal root ganglia (DRGs) and its correlations with growth-associated protein 43 (GAP-43)–positive intraepidermal nerve fibres (IENFs) and behavioural data. Plot of the time course of GAP-43–positive IENFs in the left paw pad skin and ED1 immunoreactivity (macrophage invasion) in the lumbar DRGs (a). Correlation between ED1-immunoreactive cells in the DRGs and weight-bearing. Relative weight bearing for control animals was defined as 50 %, with equal weight on both legs. Control values are parenthesized (b). Correlation between ED1-immunoreactive cells in the DRGs and primary hyperalgesia. Control values in parentheses were set at 234.5 g, which was the average baseline value from animals before induction of AIA (SD was ±20.6 g) (c). Relationship of ED1 immunoreactivity and secondary hyperalgesia in the paw. Control values in parentheses were determined as the mean of baseline values from acute and chronic AIA animals before induction of AIA (27.9 g ± 7.6 g) (d)
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Fig9: Anti-CD68 antibody (ED1) immunoreactivity in lumbar dorsal root ganglia (DRGs) and its correlations with growth-associated protein 43 (GAP-43)–positive intraepidermal nerve fibres (IENFs) and behavioural data. Plot of the time course of GAP-43–positive IENFs in the left paw pad skin and ED1 immunoreactivity (macrophage invasion) in the lumbar DRGs (a). Correlation between ED1-immunoreactive cells in the DRGs and weight-bearing. Relative weight bearing for control animals was defined as 50 %, with equal weight on both legs. Control values are parenthesized (b). Correlation between ED1-immunoreactive cells in the DRGs and primary hyperalgesia. Control values in parentheses were set at 234.5 g, which was the average baseline value from animals before induction of AIA (SD was ±20.6 g) (c). Relationship of ED1 immunoreactivity and secondary hyperalgesia in the paw. Control values in parentheses were determined as the mean of baseline values from acute and chronic AIA animals before induction of AIA (27.9 g ± 7.6 g) (d)

Mentions: We next examined potential correlations between ED1 in the lumbar DRGs and GAP-43–positive IENFs in the paw pad and between ED1 and pain-related behaviour. Figure 9a demonstrates the increased ED1 immunoreactivity and therewith invasion of macrophages into the lumbar DRGs in the acute phase of AIA and its decline back to the level of control values in the chronic phase. Numbers of GAP-43–positive IENFs started to increase in the acute stage of AIA and were strongly elevated in the chronic stage. The plot in Fig. 9 clearly depicts a lack of strict correlation between macrophages in the DRGs and the density of GAP-43–positive IENFs at this time point.Fig. 9


Antigen-induced arthritis in rats is associated with increased growth-associated protein 43-positive intraepidermal nerve fibres remote from the joint.

Jochmann E, Boettger MK, Anand P, Schaible HG - Arthritis Res. Ther. (2015)

Anti-CD68 antibody (ED1) immunoreactivity in lumbar dorsal root ganglia (DRGs) and its correlations with growth-associated protein 43 (GAP-43)–positive intraepidermal nerve fibres (IENFs) and behavioural data. Plot of the time course of GAP-43–positive IENFs in the left paw pad skin and ED1 immunoreactivity (macrophage invasion) in the lumbar DRGs (a). Correlation between ED1-immunoreactive cells in the DRGs and weight-bearing. Relative weight bearing for control animals was defined as 50 %, with equal weight on both legs. Control values are parenthesized (b). Correlation between ED1-immunoreactive cells in the DRGs and primary hyperalgesia. Control values in parentheses were set at 234.5 g, which was the average baseline value from animals before induction of AIA (SD was ±20.6 g) (c). Relationship of ED1 immunoreactivity and secondary hyperalgesia in the paw. Control values in parentheses were determined as the mean of baseline values from acute and chronic AIA animals before induction of AIA (27.9 g ± 7.6 g) (d)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4621858&req=5

Fig9: Anti-CD68 antibody (ED1) immunoreactivity in lumbar dorsal root ganglia (DRGs) and its correlations with growth-associated protein 43 (GAP-43)–positive intraepidermal nerve fibres (IENFs) and behavioural data. Plot of the time course of GAP-43–positive IENFs in the left paw pad skin and ED1 immunoreactivity (macrophage invasion) in the lumbar DRGs (a). Correlation between ED1-immunoreactive cells in the DRGs and weight-bearing. Relative weight bearing for control animals was defined as 50 %, with equal weight on both legs. Control values are parenthesized (b). Correlation between ED1-immunoreactive cells in the DRGs and primary hyperalgesia. Control values in parentheses were set at 234.5 g, which was the average baseline value from animals before induction of AIA (SD was ±20.6 g) (c). Relationship of ED1 immunoreactivity and secondary hyperalgesia in the paw. Control values in parentheses were determined as the mean of baseline values from acute and chronic AIA animals before induction of AIA (27.9 g ± 7.6 g) (d)
Mentions: We next examined potential correlations between ED1 in the lumbar DRGs and GAP-43–positive IENFs in the paw pad and between ED1 and pain-related behaviour. Figure 9a demonstrates the increased ED1 immunoreactivity and therewith invasion of macrophages into the lumbar DRGs in the acute phase of AIA and its decline back to the level of control values in the chronic phase. Numbers of GAP-43–positive IENFs started to increase in the acute stage of AIA and were strongly elevated in the chronic stage. The plot in Fig. 9 clearly depicts a lack of strict correlation between macrophages in the DRGs and the density of GAP-43–positive IENFs at this time point.Fig. 9

Bottom Line: However, paw skin and back skin revealed a significantly higher number of nerve fibres expressing GAP-43 at both the acute and chronic stages of AIA.Although the innervation of the skin remote from the joint did not show significant abnormalities of the other nerve fibre markers, the rapid and persistent increase of GAP-43 expression is conspicuous.The data suggest that immune-mediated arthritis is associated with changes in skin innervation remote from the inflamed joint, although the skin is not inflamed, which may contribute to symptoms in nonarticular tissue remote from the affected joint.

View Article: PubMed Central - PubMed

Affiliation: Institute of Physiology 1/Neurophysiology, Jena University Hospital, Friedrich Schiller University, Teichgraben 8, 07743, Jena, Germany. elisabeth.jochmann@med.uni-jena.de.

ABSTRACT

Introduction: Pain in arthritis may be experienced in regions outside the affected joint, and hyperalgesia may even be widespread. The spread of pain is usually attributed to mechanisms in the central nervous system. We investigated whether rats with antigen-induced arthritis (AIA) exhibit peripheral changes in skin innervation remote from the inflamed joint.

Methods: After immunization, unilateral AIA in the knee joint was induced in rats. Intraepidermal nerve fibre density was determined by immunohistochemical staining for protein gene product 9.5 (PGP 9.5) and for nerve fibres expressing calcitonin gene-related peptide (CGRP), substance P (SP), transient receptor potential vanilloid 1 (TRPV1; the heat and capsaicin receptor), β-tubulin, and growth-associated protein 43 (GAP-43; a marker of regenerating nerve fibres) in paw pad skin and back skin. Cluster of differentiation 11b (CD11b)-positive macrophages and CD3-positive T cells were quantified in skin, and macrophages were quantified in the lumbar dorsal root ganglia. In addition, pain-related behaviour was assessed.

Results: Intraepidermal nerve fibre density (PGP 9.5) and the numbers of fibres expressing CGRP, SP, TRPV1, or β-tubulin did not show a significant change in the acute (3 days) or chronic phase (21 days) of AIA compared with control rats that were only immunized. However, paw skin and back skin revealed a significantly higher number of nerve fibres expressing GAP-43 at both the acute and chronic stages of AIA. The skin of arthritic rats in these regions did not contain a greater density of CD11b and CD3 immune cells than the skin of control rats. Enhanced expression of GAP-43 in nerve fibres of the skin was not related to hyperalgesia in the joint, but it accompanied persistent secondary cutaneous hyperalgesia in the skin remote from the inflamed joint.

Conclusions: Although the innervation of the skin remote from the joint did not show significant abnormalities of the other nerve fibre markers, the rapid and persistent increase of GAP-43 expression is conspicuous. The data suggest that immune-mediated arthritis is associated with changes in skin innervation remote from the inflamed joint, although the skin is not inflamed, which may contribute to symptoms in nonarticular tissue remote from the affected joint.

No MeSH data available.


Related in: MedlinePlus