Abstract
BackgroundExcessive inflammation within damaged tissue usually leads to delayed or insufficient regeneration, and nerves in the peripheral nervous system (PNS) generally do not recover fully following damage. Consequently, there is growing interest in whether modulation of the inflammatory response could help to promote nerve regeneration in the PNS. However, to date, there are no practical therapeutic strategies for manipulating inflammation after nerve injury. Thrombomodulin (TM) is a transmembrane glycoprotein containing five domains. The lectin-like domain of TM has the ability to suppress the inflammatory response. However, whether TM can modulate inflammation in the PNS during nerve regeneration has yet to be elucidated.MethodsWe investigated the role of TM in switching proinflammatory type 1 macrophages (M1) to anti-inflammatory type 2 macrophages (M2) in a human monocytic cell line (THP-1) and evaluated the therapeutic application of TM in transected sciatic nerve injury in rats.ResultsThe administration of TM during M1 induction significantly reduced the expression levels of inflammatory cytokines, including TNF-a (p < 0.05), IL-6 (p < 0.05), and CD86 (p < 0.05), in THP-1 cells. Simultaneously, the expression levels of M2 markers, including IL-10 (p < 0.05) and CD206 (p < 0.05), were significantly increased in TM-treated THP-1 cells. Inhibition of IL-4R-c-Myc-pSTAT6-PPARγ signaling abolished the expression levels of IL-10 (p < 0.05) and CD206 (p < 0.05). The conditioned medium (CM) collected from M1 cells triggered an inflammatory response in primary Schwann cells, while CM collected from M1 cells treated with TM resulted in a dose-dependent reduction in inflammation. TM treatment led to better nerve regeneration when tested 6 weeks after injury and preserved effector muscle function. In addition, TM treatment reduced macrophage infiltration at the site of injury and led to potent M1 to M2 transition, thus indicating the anti-inflammatory capacity of TM.ConclusionsCollectively, our findings demonstrate the anti-inflammatory role of TM during nerve regeneration. Therefore, TM represents a potential drug for the promotion and modulation of functional recovery in peripheral nerves that acts by regulating the M1/M2 ratio.
Highlights
Excessive inflammation within damaged tissue usually leads to delayed or insufficient regeneration, and nerves in the peripheral nervous system (PNS) generally do not recover fully following damage
TM inhibited M1 inflammatory cytokine production and caused a switch toward the M2 phenotype The combination of LPS and IFN-γ induction led to an M1 macrophage phenotype; cells produced high levels of prototypical M1 cytokines, including Tumor necrosis factor α (TNF-α), IL1β, and IL-6 (Fig. 1b)
The quantitative polymerase chain reaction (qPCR) results showed that the administration of TM led to a significant decrease in the expression of TNF-α, IL-1β, IL-6, and CD86 and a concomitant increase in the expression of genes encoding the M2 macrophage markers IL-10 and CD206 (Fig. 1c)
Summary
Excessive inflammation within damaged tissue usually leads to delayed or insufficient regeneration, and nerves in the peripheral nervous system (PNS) generally do not recover fully following damage. There is growing interest in whether modulation of the inflammatory response could help to promote nerve regeneration in the PNS. Whether TM can modulate inflammation in the PNS during nerve regeneration has yet to be elucidated. A previous study showed that mice lacking Toll-like receptor 2 (TLR2) or TLR4 failed to produce IL-1β following nerve ligation. These mice showed reduced levels of macrophage infiltration at the injury site, resulting in the impairment of myelin clearance, axonal regeneration, and functional recovery [2]. As a result of the double-edged properties of inflammation, there is growing interest in targeting the modulation of inflammation for the treatment of nerve injuries [5]
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