HGF-mediated functional supression of toll-like receptors in an innate immune system under ischemic diseases

2015 Fiscal Year Final Research Report

• Project/Area Number: 23590458
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Osaka University
• Principal Investigator: Mizuno Shinya 大阪大学, 医学(系)研究科(研究院), 助教 (10219644)
• Co-Investigator(Renkei-kenkyūsha): NAKAMURA TOSHIKAZU 大阪大学, 先端科学イノベーションセンター, 特任教授 (00049397)
• Project Period (FY): 2011-04-28 – 2016-03-31
• Keywords: HGF / c-Met / 虚血性疾患 / トール様受容体 / マクロファージ / TLR4 / HMGB1

Outline of Final Research Achievements

HGF improves pathological conditions during ischemic organ diseases through inducing anti-apoptotic and regenerative properties. There is now emerging evidence to show that over-activation of “innate immune system” by HMGB1 triggers excessive inflammatory events and accelerates organ dysfunction. Using a mouse model of renal ischemia, we demonstrated that HGF-mediated anti-apoptotic outcomes in parenchaymal cells leads to the suppression of extra-cellular HMGB1 secretion. Furthermore, we found that HGF directly targeted macrophages to intercept HMGB1-TLR4 signaling transduction, followed by the repression in NF-κB activations. Overall, we delineated the new functions of HGF, such as (i) inhibition of HMGB1-primed activation of TLR4 downstream (i.e., receptor side) and (ii) suppression of HMGB1 secretion from dying cells (i.e., ligand side) as well. Such a dual property of HGF likely contributes to the improvement in ischemic organ disorders.

Free Research Field

実験病理学