High mobility group box 1 secretion blockade results in the reduction of early pancreatic islet graft loss

Hyunwoo Chung, Sung Ji Hong, So Won Choi, Ja Young Koo, Mingi Kim, Hyun Je Kim, Seung Bum Park, Chung Gyu Park

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Abstract

Pancreatic islet transplantation has been known as the best cure for patients suffering from severe type 1 diabetes mellitus (T1DM). Despite meaningful advances in human allogeneic islet transplantation field, significant amounts of islet loss in early post-transplantation periods is still a big concern for clinicians. One of the major factors determining the fate of the islets is the danger-associated molecular patterns (DAMPs)secreted by activated immune cells or islets themselves under hypoxic stress. High mobility group box 1 (HMGB1)protein is one of the best characterized DAMP molecules associated with islets. HMGB1 is known to be passively released by transplanted murine islet cells after taking damages from cytokines, reactive oxygen species, and other DAMPS, and the released HMGB1 harms neighboring islet cells by interacting with receptors expressed on murine islets such as toll-like receptor 2 (TLR2)and TLR4, thereby forming a vicious cycle. Here, we show that a small molecule inhibitor inflachromene (ICM)was capable of blocking the secretion of HMGB1 from murine islet cells during the normoxic and hypoxic post-isolation period. Notably, the treatment of ICM during the islet isolation process resulted in decreased HMGB1 levels during the subsequent cell culture. ICM's in vivo efficacy was evaluated in murine syngeneic islet transplantation model, and it significantly reduced the serum and graft level of HMGB1. Ultimately, the intraperitoneal administration of ICM prevented the loss of marginal-mass islet grafts and reversed the diabetes in mice.

Original languageEnglish
Pages (from-to)1081-1086
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume514
Issue number4
DOIs
StatePublished - 5 Jul 2019

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Keywords

  • DAMP
  • HMGB1
  • Hypoxia
  • Islet transplantation

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