Roles of HMGB1, a nuclear protein, in axonal regeneration after nerve injury

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08325
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: Kindai University
• Principal Investigator: Sekiguchi Fumiko 近畿大学, 薬学部, 准教授 (90271410)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: HMGB1 / 神経突起伸長 / thrombomodulin / thrombin / RAGE / 神経損傷 / angiopoiethin-1

Outline of Final Research Achievements

The data in the present study suggest that HMGB1 induces neurite outgrowth via activation of RAGE in mouse dorsal root ganglion (DRG) neurons, and that macrophage-derived HMGB1 contributes to increase in neurite outgrowth observed in DRG neurons after crush of sciatic nerves. In addition, the data also show that thrombomodulin-alfa (TMα), which is a recombinant soluble form of TM, a membrane protein expressed in the endothelial cells, suppresses the HMGB1-induced neurite outgrowth via adsorption of HMGB1 and also via facilitation of degradation of HMGB1 induced by thrombin (TB), the effects abolished by antiopoietin-1, known to inhibit the binding of TB to TM. The information may be useful for establishment of novel therapeutic strategies for axonal regeneration after nerve injury.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

細胞外へ放出されたHMGB1はRAGEやTLR4を含む数種類の受容体を介して炎症および疼痛の発症に寄与するため、HMGB1の中和抗体や受容体阻害薬、HMGB1の吸着と分解を促進するTMαなどが炎症や難治性疼痛の治療を目的とした新薬の候補物質として開発が進められている。しかし、HMGB1/RAGE経路が神経軸索再生において重要な役割を担っていることを示す本研究の結果を考慮すると、神経損傷を伴う炎症や疼痛の治療において、HMGB1そのものの減少は神経再生にマイナスになることが示唆される。本研究で得られた知見はHMGB1を標的とした治療戦略を立てる上で考慮すべき重要な内容である。