Thrombomodulin facilitates peripheral nerve regeneration through regulating M1/M2 switching

Background: 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. 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. Methods: We 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. Results: The 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-PPARγsignaling 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. Conclusions: Collectively, 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.