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Comparative Study
. 2005 Oct;167(1-2):13-22.
doi: 10.1016/j.jneuroim.2005.06.013.

Increase in inflammatory cytokines in median nerves in a rat model of repetitive motion injury

Talal Al-Shatti  1 , Ann E Barr, Fayez F Safadi, Mamta Amin, Mary F Barbe
Affiliations
Comparative Study

Increase in inflammatory cytokines in median nerves in a rat model of repetitive motion injury

Talal Al-Shatti et al. J Neuroimmunol. 2005 Oct.

Abstract

We examined cytokines in rat median nerves following performance of a high repetition reaching and grasping task at a rate of 8 reaches/min for up to 8 weeks. IL-1alpha, IL-1beta, TNF-alpha, IL-6 and IL-10 were analyzed by immunohistochemistry. Double-labeling immunohistochemistry for ED1, a marker of phagocytic macrophages, was also performed. We found increased immunoexpression of IL-6 by week 3, increases in all 5 cytokines by week 5. This response was transient as all cytokines returned to control levels by 8 weeks of performance of a high repetition negligible force task. Cytokine sources included Schwann cells, fibroblasts and phagocytic macrophages (ED1-immunopositive). These findings suggest that cytokines are involved in the pathophysiology of repetitive motion injuries in peripheral nerves.

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Figures

Fig. 1
Fig. 1
Histograms showing quantification of immunohistochemical staining of IL-1α (A), IL1β (B), TNF-α (C) and IL-6 (D). The percent area fraction of digitized nerve sections containing cytokine immunostaining was quantified in median nerves at the point that they spanned the carpal tunnel, in control rats and in rats that had performed a HRNF task for 3, 5 or 8 weeks. The region of nerve measured lay within the boundaries of the sectioned median nerve (N) and surrounding epineurium (E), excluding surrounding tissues such as loose connective tissue (CT), as shown in panels E and F. The green line demarcates the region of interest (ROI) measured in this nerve section (panel F). The blue color in panel F indicates the pixels in the ROI that contained brown immunoreaction product (shown in panel E) that meet the defined threshold of immunostaining. The percent area fractions of the area containing thresholded pixels versus the area of the entire ROI are shown in A - D and are expressed as mean + SEM. Data from normal control rats and shaped-only control rats are combined and are referred to as C. The number of reach limb nerves quantified for controls, or per task week, are: n = 3 - 9 for control rats, n = 3 - 5 for week 3, n = 3 - 5 for week 5, and n = 3 - 4 for week 8, depending on the cytokine. *Significantly different from week 0 ( p ≤ 0.001). Scale bar in panel E = 50 μm.
Fig. 2
Fig. 2
Immunohistochemical localization of IL-1α, IL-1β, TNF-α and IL-6 in the median nerves from normal control rats (C) or from reach limbs of rats that performed a HRNF task for 5 weeks. No immunostaining for these cytokines is visible in the normal, control rat nerves (A, C, E, G). In nerves collected from the HRNF week 5 rats (B, D, F, H), cytokine protein immunoexpression is increased in a variety of cell types. The large dark-blue arrows in panels B, D, F and H indicate examples of immunoreactive Schwann cells. Black arrowheads indicate examples of immunoreactive cells resembling macrophages (m) or fibroblasts (f). The small black arrows in panel B indicate examples of axons located within Nodes of Ranvier, all of which are immuno-negative for IL-1α. The inset of panel B, a higher power photo, also shows that IL-1α is not expressed in the axon. In contrast, the small black arrows in panel D and its inset indicate examples of axons at sites of Nodes of Ranvier that are immunoreactive for IL-1β. The asterisk in panel D indicates an area that is further enlarged in the inset of panel D. Scale bars = 50 μm.
Fig. 3
Fig. 3
Immunohistochemical localization of IL-10 in median nerves of either a normal control rat (A) or in the reach limb of rats that performed a HRNF task for 5 weeks. No immunostaining for IL-10 is visible in the normal, control rat nerve (A). In nerves collected from HRNF week 5 rats (B - E), IL-10 immunoexpression is localized only to cells resembling macrophages (m). IL-10 immunoreactive cell shown in panel C also expresses ED1, a marker of infiltrating, phagocytic macrophages (D). Panel E shows a merger of photos C and D. Scale bars in A and B = 50 μm; scale bar is panel C = 25 μm.
Fig. 4
Fig. 4
Immunoflourescent photomicrographs showing co-localization of cytokines with ED1-positive cells (macrophages), in reach limb median nerve from rats that performed a HRNF task for 5 weeks. Panels in A, D, and G show nerve cells immunoreactive for IL-1α, IL-1β and TNF-α. Small white arrowheads in panels A and D indicate cells immunoreactive for IL-1α, IL-1β and TNF-α, respectively, that are also immunoreactive for ED1, as shown in panels B, E and I. Panels C, F, and I show co-localization in merged photos. The larger white arrowhead in panel H indicates an ED1-positive macrophage that is not double-labeled for TNF-α (G and I). Scale bars in each panel = 50 μm.
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