Thrombomodulin-Induced Prevention of Peripheral Neuropathy in Oxaliplatin-Treated Mice Involves Complement C5a Inactivation and PAR1 Activation in Addition To HMGB1 Degradation

High mobility group box 1 (HMGB1), a nuclear protein, once released to the extracellular space, participates in the pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN). Thrombomodulin alfa (TMα), a recombinant soluble protein of endothelial thrombomodulin, prevents CIPN by promoting thrombin-dependent HMGB1 degradation and activation of protein C and thrombin-activatable fibrinolysis inhibitor (TAFI/plasma carboxypeptidase B/CPB2). We thus investigated the downstream molecules of activated protein C (APC) and TAFI (TAFIa), for prevention of oxaliplatin-induced peripheral neuropathy (OIPN) in mice. OIPN was prevented by TMα and by each of an anti-HMGB1-neutralizing antibody (HAb), APC and porcine pancreatic carboxypeptidase B (ppCPB, used as a stable surrogate of TAFIa), or their combination at subeffective doses. Intraplantar administration of HMGB1 induced mechanical allodynia, which was abolished by TMα, but not APC or ppCPB. The anti-OIPN effects of TMα and APC were reversed by an antagonist of proteinase-activated receptor 1 (PAR1), targetable by APC, and the effect of TMα was also reversed by a CPB inhibitor. Intraplantar administration of mouse C5a (mC5a), targetable by TAFIa, caused mechanical allodynia, an effect blocked by TMα, a mC5a receptor (mC5aR) antagonist or HAb. The mC5aR antagonist prevented OIPN development. Oxaliplatin significantly increased plasma C5a levels in the mice treated with argatroban, a thrombin inhibitor, capable of reducing the degradation of HMGB1 by the endogenous thrombin-thrombomodulin axis. Our data thus suggest that the anti-OIPN effect of TMα involves APC-induced PAR1 activation and TAFIa-induced degradation of C5a that induces HMGB1-dependent pain, in addition to HMGB1 degradation.

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In oxaliplatin-treated mice, recombinant thrombomodulin alfa prevented peripheral neuropathy through HMGB1 degradation together with activated protein C/PAR1 signalling and TAFIa-mediated complement C5a inactivation, suggesting additional mechanisms beyond HMGB1 clearance alone.

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