Biochemical and Biophysical Research Communications
High mobility group box 1 secretion blockade results in the reduction of early pancreatic islet graft loss
Introduction
Pancreatic islet transplantation has now become a routine procedure for T1DM patients with hypoglycemia unawareness, severe hypoglycemic episodes, and glycemic liability [1]. Despite scientific and technical advances so far, the loss of implanted islet mass in the early period of transplantation is still inevitable, thus requiring two to three donors to cure one diabetic patient [2]. Previous reports connected this misfortune to the hypoxic stress inflicted upon the islet graft and the vulnerability of the pancreatic islets to the stress [3]. Because of the low-oxygen tension of the implantation sites [4] and low revascularization rate of islet grafts [5], hypoxic stress against islets is unavoidable. Hence, reducing the hypoxia-related damage in the entire islet isolation and transplantation procedure would be critical for the successful engraftment of pancreatic islets.
It is well known that many DAMPs are released following cell death due to hypoxic damage, and they again accelerate the destruction of transplanted islets [6]. HMGB1 is a nuclear protein involved in chromatin stabilization and transcription process, but it has been also known to act as a DAMP when released to the extracellular environment at times of immune activation or cell death [7]. In fact, HMGB1 is highly associated with hypoxia-induced islet cell loss either through direct binding to the islets via TLR2 or TLR4 engagement [8]. Naturally, there were attempts to prevent the loss of pancreatic islet graft by blocking the secretion of HMGB1 [9] or neutralizing its effect [10]. Many of these efforts succeeded in protecting islet graft and reversed the diabetes in mice [[11], [12], [13]], which re-emphasizes the detrimental function of extracellular HMGB1 in islet transplantation settings.
In this study, we tested whether ICM, a small-molecule inhibitor of HMGB1 previously known to block the HMGB1 secretion in neuro-inflammatory cells with great potency and little toxicity [14], could work in the same manner on pancreatic islets in vitro and islet transplantation in vivo. We discovered that ICM could block the secretion of HMGB1 in isolated pancreatic islets, and showed that the HMGB1 blockade by ICM could spare the mass of islet grafts in diabetic mice recipients.
Section snippets
Animals
Female BALB/cAnHsd (BALB/c) mice at 8–12 weeks of age were purchased from Jackson Laboratories (Bar Harbor, ME) and maintained in the Seoul National University specific pathogen-free (SPF) animal facilities. All experimental procedures were conducted in accordance with the guidelines outlined in the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources (NIH Publication No. 86–23, revised 2011) and published by the National Institute of Health.
ICM reduces the level of HMGB1 in islet cultures
The first step we took was to determine whether ICM could demonstrate the same potency to pancreatic islets as it did to the microglia. Since islets express the receptors for LPS [8,10], we sought to investigate the ICM's effect on LPS-treated MIN6 cells. Through ICC, we observed that ICM treatment reduced the expression of LPS-induced HMGB1 in MIN6 cells (Fig. 1A). Particularly, HMGB1 seemed to localize to the nuclear compartment of the cells after ICM treatment (white arrows). In fact, ICM
Discussion
Here, we tried to show that usage of ICM, a small-molecule inhibitor of HMGB1, has certain gains in murine islet transplantation. Recently, ICM was proven to be effective in the sepsis treatment [15], indicating that it could be used on the broader spectrum of HMGB1-secreting cells. We speculated that ICM could be used in pancreatic islet transplantation settings, where pancreatic islets act as a substantial reservoir of HMGB1 protein [20,23] and increased serum level of HMGB1 is negatively
Acknowledgements
This work was supported by a grant from the Korea Healthcare Technology R&D Project through the Korea Health Industry Development Institute and funding from the Ministry for Health and Welfare, Republic of Korea (Grant No. HI13C0954). This work also was supported by the Creative Research Initiative Grant (2014R1A3A2030423) and the Bio & Medical Technology Development Program (2012M3A9C4048780) through the National Research Foundation of Korea funded by the Ministry of Science & ICT, Korea.
References (26)
- et al.
Clinical pancreatic islet transplantation
Nat. Rev. Endocrinol.
(2017) - et al.
Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen
N. Engl. J. Med.
(2000) - et al.
Low temperature condition prevents hypoxia-induced islet cell damage and HMGB1 release in a mouse model
Cell Transplant.
(2012) - et al.
Bioengineered sites for islet cell transplantation
Curr. Diabetes Rep.
(2013) - et al.
Construction of EMSC-islet co-localizing composites for xenogeneic porcine islet transplantation
Biochem. Biophys. Res. Commun.
(2018) - et al.
DAMP production by human islets under low oxygen and nutrients in the presence or absence of an immunoisolating-capsule and necrostatin-1
Sci. Rep.
(2015) - et al.
High mobility group box protein 1 (HMGB1): the prototypical endogenous danger molecule
Mol. Med.
(2015) - et al.
Islet-expressed TLR2 and TLR4 sense injury and mediate early graft failure after transplantation
Eur. J. Immunol.
(2010) - et al.
Pretreatment of donor islets with the Na+/Ca2+ exchanger inhibitor improves the efficiency of islet transplantation
Am. J. Transplant.
(2013) - et al.
TLR4 mediates early graft failure after intraportal islet transplantation
Am. J. Transplant.
(2010)
Prevention of high-mobility group box 1-mediated early loss of transplanted mouse islets in the liver by antithrombin III
Transplantation
Efficacy of DHMEQ, a NF-κB inhibitor, in islet transplantation: I. HMGB1 suppression by DHMEQ prevents early islet graft damage
Transplantation
HMGB1-Mediated early loss of transplanted islets is prevented by anti–IL-6r antibody in mice
Pancreas
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The blockade of cytoplasmic HMGB1 modulates the autophagy/apoptosis checkpoint in stressed islet beta cells
2021, Biochemical and Biophysical Research CommunicationsCitation Excerpt :The differences between groups were compared by Student’s t-test or Mantel-Cox test. Since we confirmed in our last study [18] that ICM could block HMGB1 release from hypoxic primary islets, we thus expected the viability of the islets in the same condition to rise. However, it was discovered that ICM treatment (10 μM) could not rescue the viability of primary islets under hypoxia (Fig. 1A), and the outcome was similar in MIN6 cells (Fig. 1B).
Toll-like receptor 2-modulating pectin-polymers in alginate-based microcapsules attenuate immune responses and support islet-xenograft survival
2021, BiomaterialsCitation Excerpt :Furthermore, many islet-cells in the capsules undergo necrosis and necroptosis due to damage done to the islets during the enzymatic isolation from the pancreas, which may be exacerbated by surgery-induced pro-inflammatory environment in the transplantation site [26,29–32]. The damaged cells secrete cytokines [33], but also highly pro-inflammatory molecules such as so-called danger-associated molecular patterns (DAMPs), e.g., DNA fragments, uric acid, high mobility group box 1 (HMGB1), and heat shock proteins (HSPs) [34–37]. These DAMPs subsequently stimulate a cascade of pro-inflammation signaling pathways and induce activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [38], leading to production of pro-inflammatory cytokines and chemokines [36].
Mechanistic insights into dimethyl cardamonin-mediated pharmacological effects: A double control of the AMPK-HMGB1 signaling axis
2020, Life SciencesCitation Excerpt :Parenthetically, in our modeling analysis we found that DMC occupies the same binding pocket that the well-characterized drug inflachromene which has been shown to bind to HMGB1 and to down-regulate its proinflammatory functions and to reduce neuronal damages in vivo [54]. As a HMGB1 regulatory agent, this drug is considered as an interesting lead for the design of molecules effective against sepsis [55] and to prevent the loss of pancreatic islet grafts in patients suffering from severe type 1 diabetes mellitus [56]. Therefore, with a similar mode of action, the use of DMC in these indications should be evaluated as well.
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Hyun-Je Kim's Current address is, Department of Dermatology and the Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.