レプチン受容体遺伝子欠損および高脂肪食摂取による2型糖尿病モデルマウスの有痛性末梢神経障害へのHMGB1とアナフィラトキシンC5aの関与について

抄録

We have demonstrated that high mobility group box 1 (HMGB1) derived from macrophages (Mφ) and anaphylatoxin C5a participate in chemotherapy-induced peripheral neuropathy, which is prevented by thrombomodulin alfa (TMα) that causes thrombin-dependent HMGB1 degradation and thrombin-activatable fibrinolysis inhibitor (TAFI) activation. Thus, we investigated possible involvement of HMGB1 and C5a degradable by the activated TAFI (TAFIa) in the development of diabetic peripheral neuropathy (DPN) in mice with diabetes mellitus (DM). Repeated administration of TMα or an anti-HMGB1-neutralizing antibody prevented DPN development in type 2 DM (T2DM) models, i.e. leptin receptor-deficient db/db mice and high fat diet/low dose streptozotocin (STZ)-induced DM mice, but not in STZ-induced type 1 DM mice. Ethyl pyruvate able to inhibit HMGB1 release from Mφ, minocycline, a Mφ/microglia inhibitor, liposomal clodronate, a Mφ depletor, and DF2593A, a C5a receptor (C5aR) antagonist, reduced or abolished DPN development in the T2DM mice that had upregulation of C5aR, but not HMGB1, in the sciatic nerve. Our data suggest that Mφ-derived HMGB1 and C5a/C5aR participate in DPN development accompanying T2DM, which can be prevented by TMα that causes thrombin-dependent inactivation of HMGB1 and activation of TAFI followed by C5a degradation.