Capsaicin-sensitive sensory nerves exert complex regulatory functions in the serum-transfer mouse model of autoimmune arthritis - PubMed (original) (raw)

Capsaicin-sensitive sensory nerves exert complex regulatory functions in the serum-transfer mouse model of autoimmune arthritis

Éva Borbély et al. Brain Behav Immun. 2015 Mar.

Abstract

Objective: The K/BxN serum-transfer arthritis is a widely-used translational mouse model of rheumatoid arthritis, in which the immunological components have thoroughly been investigated. In contrast, little is known about the role of sensory neural factors and the complexity of neuro-immune interactions. Therefore, we analyzed the involvement of capsaicin-sensitive peptidergic sensory nerves in autoantibody-induced arthritis with integrative methodology.

Methods: Arthritogenic K/BxN or control serum was injected to non-pretreated mice or resiniferatoxin (RTX)-pretreated animals where capsaicin-sensitive nerves were inactivated. Edema, touch sensitivity, noxious heat threshold, joint function, body weight and clinical arthritis severity scores were determined repeatedly throughout two weeks. Micro-CT and in vivo optical imaging to determine matrix-metalloproteinase (MMP) and neutrophil-derived myeloperoxidase (MPO) activities, semiquantitative histopathological scoring and radioimmunoassay to measure somatostatin in the joint homogenates were also performed.

Results: In RTX-pretreated mice, the autoantibody-induced joint swelling, arthritis severity score, MMP and MPO activities, as well as histopathological alterations were significantly greater compared to non-pretreated animals. Self-control quantification of the bone mass revealed decreased values in intact female mice, but significantly greater arthritis-induced pathological bone formation after RTX-pretreatment. In contrast, mechanical hyperalgesia from day 10 was smaller after inactivating capsaicin-sensitive afferents. Although thermal hyperalgesia did not develop, noxious heat threshold was significantly higher following RTX pretreatment. Somatostatin-like immunoreactivity elevated in the tibiotarsal joints in non-pretreated, which was significantly less in RTX-pretreated mice.

Conclusions: Although capsaicin-sensitive sensory nerves mediate mechanical hyperalgesia in the later phase of autoantibody-induced chronic arthritis, they play important anti-inflammatory roles at least partially through somatostatin release.

Keywords: Capsaicin-sensitive sensory nerves; Inflammation; Matrix-metalloproteinase; Pain; Somatostatin.

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

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Figures

Supplementary Fig. 1

Supplementary Fig. 1

Serum-induced weight loss and impaired joint function: data points represent the percentage change of weight loss of male (A) and female (B) mice compared to the initial control values and the absolute values of time spent on the grid for male (C) and female animals (D) (n = 4–5/control groups, n = 6–8/arthritic groups; two-way ANOVA + Bonferroni’s modified _t_-test).

Fig. 1

Fig. 1

Serum-induced edema and arthritis score throughout the 2 weeks experimental period. Data points represent the percentage increase of the paw volume of male (A) and female (B) mice compared to the initial control values and the absolute values of arthritis scores for male (C) and female animals (D) (n = 4–5/non-inflamed groups, n = 6–8/arthritic groups; ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001 vs. non-pretreated; two-way ANOVA + Bonferroni’s modified _t_-test).

Fig. 2

Fig. 2

Serum-induced hyperalgesia throughout the 2 weeks experimental period. Data points represent the percentage decrease of mechanonociceptive threshold for male (A) and female (B) mice, and the absolute values of noxious heat threshold for male (C) and female animals (D) (n = 4–5/control non-inflamed groups, n = 6–8/arthritic groups; ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001 vs. non-pretreated; two-way ANOVA + Bonferroni’s modified _t_-test).

Fig. 3

Fig. 3

Change of neutrophil-derived myeloperoxidase activity. Panel (A) shows representative pretreatment control images, whereas panels (B and C) demonstrate inflammatory neutrophil activity on day 2 and 6 following arthritis induction, respectively. (D) Quantification of luminol bioluminescence in the diseased ankle joints. (n = 6–8 male mice/group, ###p < 0.001 vs. controls, ∗∗∗p < 0.001 vs. non-pretreated; Student _t_-test).

Fig. 4

Fig. 4

Matrix-metalloproteinase activity in the diseased hind limbs. (A) Representative pretreatment control images, (B and C) demonstrate inflammatory matrix-metalloproteinase activity on day 5 and 8 following arthritis induction. (D) Quantification the amount of fluorophore in the inflamed ankle joints (n = 3–4 male mice/group, ∗p < 0.05 vs. non-pretreated, + indicates that the probe was tested in intact mice in a self-control manner before the induction of the inflammation, but remained below the detection threshold; Student _t_-test).

Fig. 5

Fig. 5

Bone structural changes in the inflamed region. (A) Representative micro-CT images of the same mice, in intact state and on day 14. (B and C) Bone volume/total volume ratio in the ankle joint, expressed as raw data and as percentage of the initial self-controls. (D and E) Bone volume/total volume ratio in the distal tibia, expressed as raw data and as percentage of the initial self-controls (n = 6/group, #p < 0.05, ##p < 0.01, ###p < 0.001 vs. controls, ∗∗p < 0.01, ∗∗∗p < 0.001 vs. non-pretreated; two-way ANOVA + Dunnett and Tukey post-tests).

Fig. 6

Fig. 6

Histopathological changes of the ankle joints. Panels (A and B) show representative histopathological pictures of an intact tibiotarsal joint (ti: tibia, ta: tarsus, s: synovium), panels (C and D) demonstrate the joint structure of a non-pretreated mouse on day 14 after arthritogenic serum administration, panels (E and F) show the significantly pronounced arthritic changes of RTX-pretreated animals. (G and H) Semiquantitative histopathological scoring on the basis of synovial enlargement (white arrows), inflammatory cell accumulation (black arrows), fibroblast formation with collagen deposition (two headed arrows). Box plots represent the composite scores for male and female animals (n = 4–5/control non-inflamed groups, n = 6–8/arthritic groups; ##p < 0.01, ###p < 0.001 vs. controls, ∗p < 0.05 vs. non-pretreated; Kruskal–Wallis followed by Dunn’s post-test).

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