Abstract

Tissue damage results in the release of molecules that aid in tissue repair and produce hypersensitivity. Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), a protease inhibitor involved in extracellular matrix remodeling, contributes to neuropathic pain, but its role in modulating hypersensitivity during inflammatory conditions remains to be elucidated. To determine how inflammation regulates TIMP-1 expression in the skin we injected complete Freund's adjuvant (CFA) subcutaneously (s.c.) into the dorsal hindpaw of WT mice and found that TIMP-1 protein was significantly increased 1- and 3-dayspost-injection, a time when behavioral hypersensitivity is not observed. Therefore, we hypothesized that the release of TIMP-1 following inflammation attenuates the onset of hypersensitivity. To test this, we used global TIMP-1 knockout (T1KO) mice to examine the development of inflammatory hypersensitivity in the absence of TIMP-1. We found that T1KO mice developed hypersensitivity within 24 hours of inflammation and remained sensitive for 7 days, while WT controls developed hypersensitivity 3 days following inflammation that resolved by day 7. Ex vivo electrophysiological recordings of cutaneous sensory neurons demonstrated that T1KO afferents exhibited greater sensitivity that WT afferents. Analysis of WT and T1KO skin did not detect any genotype-specific differences in MMP-9 activity or inflammatory cytokine expression. Given that the C terminal region of TIMP-1 binds to the CD63/beta 1 Integrin receptor complex, our results suggest that TIMP-1 may attenuate hypersensitivity through a receptor-mediated signaling pathway. To explore this possibility, we injected T1KO mice with a beta 1 integrin inhibitor (Ha2/5) at the time of inflammation. We found that antagonizing beta 1 integrin reversed inflammatory hypersensitivity. Thus, our data suggest that in the absence of TIMP-1 activation of beta 1 integrin contributes to inflammatory hypersensitivity.

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