Abstract
Unresolved inflammation is a significant predictor for developing chronic pain, and targeting the mechanisms underlying inflammation offers opportunities for therapeutic intervention. During inflammation, matrix metalloproteinase (MMP) activity contributes to tissue remodeling and inflammatory signaling, and is regulated by tissue inhibitors of metalloproteinases (TIMPs). TIMP-1 and -2 have known roles in pain, but only in the context of MMP inhibition. However, TIMP-1 also has receptor-mediated cell signaling functions that are not well understood. Here, we examined how TIMP-1-dependent cell signaling impacts inflammatory hypersensitivity and ongoing pain. We found that hindpaw injection of complete Freund’s adjuvant (CFA) increased cutaneous TIMP-1 expression that peaked prior to development of mechanical hypersensitivity, suggesting that TIMP-1 inhibits the development of inflammatory hypersensitivity. To examine this possibility, we injected TIMP-1 knockout (T1KO) mice with CFA and found that T1KO mice exhibited rapid onset thermal and mechanical hypersensitivity at the site of inflammation that was absent or attenuated in WT controls. We also found that T1KO mice exhibited hypersensitivity in adjacent tissues innervated by different sets of afferents, as well as skin contralateral to the site of inflammation. Replacement of recombinant murine (rm)TIMP-1 alleviated hypersensitivity when administered at the site and time of inflammation. Administration of either the MMP inhibiting N-terminal or the cell signaling C-terminal domains recapitulated the antinociceptive effect of full-length rmTIMP-1, suggesting that rmTIMP-1inhibits hypersensitivity through MMP inhibition and receptor-mediated cell signaling. We also found that hypersensitivity was not due to genotype-specific differences in MMP-9 activity or expression, nor to differences in cytokine expression. Administration of rmTIMP-1 prevented mechanical hypersensitivity and ongoing pain in WT mice, collectively suggesting a novel role for TIMP-1 in the attenuation of inflammatory pain.
Highlights
Tissue inhibitors of matrix metalloproteinases (TIMPs) and matrix metalloproteinases (MMPs) are released during tissue damage to facilitate tissue remodeling through degradation and reorganization of the extracellular matrix (ECM) (Gardner and Ghorpade, 2003; Nagase et al, 2006; Ries, 2014)
We found that inflammation did not alter the overall expression of TIMP-1 protein in spinal cord (SC) or dorsal root ganglia (DRG), all Fs > 1.13, p > 0.05 (Figures 1A,B)
Overall TIMP-1 expression levels were unaltered in the spinal cord and DRG following inflammation, we found that TIMP-1 co-localized with glial fibrillary acidic protein (GFAP) expressing cells following inflammatory stimulation, suggesting that astrocytes (Figure 2A) and satellite glial cells (Figure 2B) appear to express TIMP-1 during inflammation (Huang et al, 2011; Welser-Alves et al, 2011)
Summary
Tissue inhibitors of matrix metalloproteinases (TIMPs) and matrix metalloproteinases (MMPs) are released during tissue damage to facilitate tissue remodeling through degradation and reorganization of the extracellular matrix (ECM) (Gardner and Ghorpade, 2003; Nagase et al, 2006; Ries, 2014) During this process MMPs engage an inflammatory response through proteolytic maturation of cytokines, and both of these activities are regulated through a 1:1 stoichiometric interaction with one of four tissue inhibitors of metalloproteinases (TIMP-1, -2, -3, -4) (Huang et al, 2011). Studies examining the role of MMPs in pain have shown that increased MMP-2 and -9 activity contribute to increased pain-related behavior in response to injury that can be reversed by MMP antagonism (Kawasaki et al, 2008; Ji et al, 2009; Li et al, 2016; Remacle et al, 2018) These findings contributed, in part, to the development of several small molecule drugs that directly target and inhibit MMP activity. While the results of these trials indicated that specific targeting of MMP activity alone is not an effective strategy for pain treatment, they suggest that additional mechanisms related to MMP activity may contribute to pain and its inhibition, and that endogenous inhibitors of MMPs, such as TIMP-1, may attenuate pain-related behavior
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