Thrombomodulin facilitates peripheral nerve regeneration through regulating M1/M2 switching

Abstract

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-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. 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.

Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NFκB to promote axonal regeneration and remyelination

“…Pro-inflammatory responses in the conduit of nerve segment were induced after 6-week post-injury in the nerve transection and silicone conduit sutured rats [ 26 , 33 ]. We observed that PBA had a beneficial effect on the inhibition of pro-inflammatory cytokines in vitro; therefore, we investigated the therapeutic potential of PBA for the modulation of inflammation in the nerve conduit after sciatic nerve transection.…”

“…The conductive microenvironment was investigated by studying the level of nerve innervation to the targeted gastrocnemius muscle as an indicator of the successful regeneration outcome [ 26 , 33 ]. The degree of nerve reinnervation was analyzed by determining the relative gastrocnemius muscle weight (RGMW) and performing a histological examination using cross-sectional image of innervated muscle tissues.…”

“…Various doses of LPS (0.1, 1, and 10 µg/ml) were used to test the inflammatory responses of SCs for 24 h. Similarly, cells at 80% confluency were treated with various doses of TNFα (0, 1, 5, and 10 ng/ml) for 24 h to confirm the initiation of inflammation. In addition, we used a human monocytic cell line (THP-1, Bioresource Collection and Research Center, Taiwan) to prepare M1-CM, according to a previously described protocol for M1 macrophage induction [ 25 , 26 ]. The freshly collected M1-CM was used to treat RT4 SCs for 24 h.…”

Microencapsulated Neural Stem Cells Inhibit Sciatic Nerve Injury-Induced Pain by Reducing P2 × 4 Receptor Expression

“…IL-1β and TNF-a are important inflammatory cytokines. Studies have shown that nerve injury can lead to an increase in the level of IL-1β and TNF-a, while reducing their release can reduce the inflammatory response of the nerve, which is beneficial to the repair of nerve injury ( Huang et al, 2020 ; Wang et al, 2020 ). Therefore, we investigated the changes in IL-1β and TNF-a in rat serum after NSC and MC-NSC transplantation.…”

STAT6 Signaling Mediates PPARγ Activation and Resolution of Acute Sterile Inflammation in Mice

“…Among these cytokines, induction of PDGF and IFN-α by zymosan stimulation has been demonstrated in macrophages and dendritic cells, respectively [43,44]. In addition, recent data suggest that the membrane-associated proteins, including ATP-binding cassette transporter A1, thrombomodulin, and Annexin A1, are involved in STAT6/PPARγ signaling pathway [45][46][47][48]. Thus, further investigation is needed to determine whether and how these proteins participate in this pathway during zymosan-induced peritonitis.…”