Reciprocal relationship between membrane type 1 matrix metalloproteinase and the algesic peptides of myelin basic protein contributes to chronic neuropathic pain

Abstract

Myelin basic protein (MBP) is an auto-antigen able to induce intractable pain from innocuous mechanical stimulation (mechanical allodynia). The mechanisms provoking this algesic MBP activity remain obscure. Our present study demonstrates that membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14) releases the algesic MBP peptides from the damaged myelin, which then reciprocally enhance the expression of MT1-MMP in nerve to sustain a state of allodynia. Specifically, MT1-MMP expression and activity in rat sciatic nerve gradually increased starting at day 3 after chronic constriction injury (CCI). Inhibition of the MT1-MMP activity by intraneural injection of the function-blocking human DX2400 monoclonal antibody at day 3 post-CCI reduced mechanical allodynia and neuropathological signs of Wallerian degeneration, including axon demyelination, degeneration, edema and formation of myelin ovoids. Consistent with its role in allodynia, the MT1-MMP proteolysis of MBP generated the MBP69-86-containing epitope sequences in vitro. In agreement, the DX2400 therapy reduced the release of the MBP69-86 epitope in CCI nerve. Finally, intraneural injection of the algesic MBP69-86 and control MBP2-18 peptides differentially induced MT1-MMP and MMP-2 expression in the nerve. With these data we offer a novel, self-sustaining mechanism of persistent allodynia via the positive feedback loop between MT1-MMP and the algesic MBP peptides. Accordingly, short-term inhibition of MT1-MMP activity presents a feasible pharmacological approach to intervene in this molecular circuit and the development of neuropathic pain.

Amino acid sequence conservation of the algesic fragment of myelin basic protein is required for its interaction with CDK5 and function in pain

“…Physical disruption of the Schwann cell–axon unit and its plasma and myelin membranes caused by nerve injury releases myelin peptides. The algesic MBP84‐104 peptide is primarily localized in Schwann cells in vivo consistent with its efficient internalization in cultured Schwann cells. The endogenous MBP peptide does not colocalize with macrophages in the postinjury nerve implying that the peptide escapes the macrophage‐mediated phagocytosis.…”

“…The algesic MBP84‐104 peptide is primarily localized in Schwann cells in vivo consistent with its efficient internalization in cultured Schwann cells. The endogenous MBP peptide does not colocalize with macrophages in the postinjury nerve implying that the peptide escapes the macrophage‐mediated phagocytosis. Inhibition of matrix metalloproteinases both blocks the MBP epitope release and diminishes pain caused by nerve injury .…”

“…The algesic MBP84‐104 cryptic epitope is released in the nerve postinjury as a result of proteolysis of MBP. In our earlier studies, the injection of the main algesic, autoimmune MBP84‐104 epitope that is hidden in the native MBP fold, into an intact nerve was sufficient to induce robust, long‐lasting allodynia in rodents . Peptides representing MBP epitope region MBP80‐99 and MBP84‐104 exhibit a high level of amino acid conservation among evolutionary distant animal species (Fig.…”

“…In the PNS, Schwann cells myelinate the nerves and synthesize MBP. Schwann cells are the main immunoreactive cell type for the algesic MBP peptide postinjury and the main cell type in the MBP‐injected nerve . Furthermore, the MBP68‐102 peptide translocates toward the paranode/node of Ranvier (NoR) of the Schwann cell–axon unit, as shown in fibers teased out from the nerve at day 1 postaxotomy (Fig.…”

“…The endogenous MBP peptide does not colocalize with macrophages in the postinjury nerve implying that the peptide escapes the macrophage‐mediated phagocytosis. Inhibition of matrix metalloproteinases both blocks the MBP epitope release and diminishes pain caused by nerve injury .…”