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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

Intraepidermal nerve fibres (IENFs) in ipsilateral rat paw pad skin. Nerve fibres immunopositive for protein gene product 9.5 (PGP 9.5) (a–c) and calcitonin gene–related peptide (CGRP) (d–f) in controls (a, d), acute AIA (b, e), and chronic AIA rats (c, f). Turquoise arrowheads indicate fine-calibre intraepidermal nerve fibres that were counted according to the European Federation of Neurological Societies' counting rules, thus visibly crossing the basement membrane between epidermis and dermis. For evaluation of IENF density, the focus of the microscope was adjusted while we analysed the individual sections. Therefore, not all IENFs that are marked by turquoise arrowheads can be followed all the way through the epidermis in the images. Thicker fibres along the dermal–epidermal junction are subepidermal nerve fibres. Numbers of IENFs that reacted with antibodies against PGP 9.5 and CGRP did not change in animals with AIA compared with immunized-only controls. Original magnification × 40
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Fig2: Intraepidermal nerve fibres (IENFs) in ipsilateral rat paw pad skin. Nerve fibres immunopositive for protein gene product 9.5 (PGP 9.5) (a–c) and calcitonin gene–related peptide (CGRP) (d–f) in controls (a, d), acute AIA (b, e), and chronic AIA rats (c, f). Turquoise arrowheads indicate fine-calibre intraepidermal nerve fibres that were counted according to the European Federation of Neurological Societies' counting rules, thus visibly crossing the basement membrane between epidermis and dermis. For evaluation of IENF density, the focus of the microscope was adjusted while we analysed the individual sections. Therefore, not all IENFs that are marked by turquoise arrowheads can be followed all the way through the epidermis in the images. Thicker fibres along the dermal–epidermal junction are subepidermal nerve fibres. Numbers of IENFs that reacted with antibodies against PGP 9.5 and CGRP did not change in animals with AIA compared with immunized-only controls. Original magnification × 40

Mentions: In rat hind paw pads and back skin, intense PGP 9.5–immunoreactive subepidermal nerve fibres of various calibres were present along the length of the dermal–epidermal junction. Many fine-calibre nerve fibres penetrated into the epidermis (IENFs), some extending almost to the stratum corneum (Fig. 2a–c, ipsilateral paw pad skin). In paw pad skin, a similar pattern was seen for CGRP-immunoreactive nerve fibres, but with clearly fewer fibres overall (Fig. 2d–f, ipsilateral paw pad skin), as well as for SP-, TRPV1-, and β-tubulin–positive fibres. These observations applied to all samples from the three groups examined (immunized controls, acute AIA, and chronic AIA), with no obvious differences in numbers of nerve fibres between groups for either marker.Fig. 2


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)

Intraepidermal nerve fibres (IENFs) in ipsilateral rat paw pad skin. Nerve fibres immunopositive for protein gene product 9.5 (PGP 9.5) (a–c) and calcitonin gene–related peptide (CGRP) (d–f) in controls (a, d), acute AIA (b, e), and chronic AIA rats (c, f). Turquoise arrowheads indicate fine-calibre intraepidermal nerve fibres that were counted according to the European Federation of Neurological Societies' counting rules, thus visibly crossing the basement membrane between epidermis and dermis. For evaluation of IENF density, the focus of the microscope was adjusted while we analysed the individual sections. Therefore, not all IENFs that are marked by turquoise arrowheads can be followed all the way through the epidermis in the images. Thicker fibres along the dermal–epidermal junction are subepidermal nerve fibres. Numbers of IENFs that reacted with antibodies against PGP 9.5 and CGRP did not change in animals with AIA compared with immunized-only controls. Original magnification × 40
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4621858&req=5

Fig2: Intraepidermal nerve fibres (IENFs) in ipsilateral rat paw pad skin. Nerve fibres immunopositive for protein gene product 9.5 (PGP 9.5) (a–c) and calcitonin gene–related peptide (CGRP) (d–f) in controls (a, d), acute AIA (b, e), and chronic AIA rats (c, f). Turquoise arrowheads indicate fine-calibre intraepidermal nerve fibres that were counted according to the European Federation of Neurological Societies' counting rules, thus visibly crossing the basement membrane between epidermis and dermis. For evaluation of IENF density, the focus of the microscope was adjusted while we analysed the individual sections. Therefore, not all IENFs that are marked by turquoise arrowheads can be followed all the way through the epidermis in the images. Thicker fibres along the dermal–epidermal junction are subepidermal nerve fibres. Numbers of IENFs that reacted with antibodies against PGP 9.5 and CGRP did not change in animals with AIA compared with immunized-only controls. Original magnification × 40
Mentions: In rat hind paw pads and back skin, intense PGP 9.5–immunoreactive subepidermal nerve fibres of various calibres were present along the length of the dermal–epidermal junction. Many fine-calibre nerve fibres penetrated into the epidermis (IENFs), some extending almost to the stratum corneum (Fig. 2a–c, ipsilateral paw pad skin). In paw pad skin, a similar pattern was seen for CGRP-immunoreactive nerve fibres, but with clearly fewer fibres overall (Fig. 2d–f, ipsilateral paw pad skin), as well as for SP-, TRPV1-, and β-tubulin–positive fibres. These observations applied to all samples from the three groups examined (immunized controls, acute AIA, and chronic AIA), with no obvious differences in numbers of nerve fibres between groups for either marker.Fig. 2

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