Early TLR4 Blockade Attenuates Sterile Inflammation-mediated Stress in Islets During Isolation and Promotes Successful Transplant Outcomes

Chang, Charles; Murphy, Kayla L.; Kane, Robert R.; Lawrence, Michael C.; Naziruddin, Bashoo

doi:10.1097/tp.0000000000002287

Cited by 15 publications

(11 citation statements)

References 49 publications

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“…OPN-305, the first humanized IgG4 monoclonal antibody against TLR-2 on monocytes, was tested in a randomized, double-blind, in-human phase I study [35]. In animal models, TAK242 pretreatment attenuated inflammation-mediated stress response and improved chronic pancreatitis and islet trans-plantation results [36]. Our results also support the combined use of TLR-2 and -4 antagonists in severely infected patients (Supporting Information Fig.…”

Section: Discussionsupporting

confidence: 66%

Kupffer cell activation by different microbial lysates: Toll‐like receptor‐2 plays pivotal role on thromboxane A₂ production in mice and humans

Zhang¹,

Lin²,

Li³

et al. 2020

Eur J Immunol

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Thromboxane (TX) A 2 has been identified as an important intrahepatic vasoconstrictor upon Kupffer cell (KC) activation during infections such as spontaneous bacterial peritonitis (SBP). The study aimed to investigate the role of TLRs in the TXA 2 increase in liver nonparenchymal cells and their related mechanisms. Here, we identified TLR-2 as a common pathway for different microbials: microbial lysates including Gram-positive bacteria, Gram-negative bacteria, and fungi all increased TXA 2 secretion via activation of TLR-2 in human KCs, accompanied by increased expression and phosphorylation of Myd88related pathway. Of all TLR agonists, only TLR-1,-2, and-4 agonists increased TXA 2 in human KCs. These results were further confirmed by mouse liver nonparenchymal cells. Comparing the effects of TLR-1,-2, and-4 antagonists, only TLR-2 antagonist showed inhibitory effects with all tested microbial lysates. Pretreatment with TLR-2 antagonist in human KCs blocked the secretion of IL-10, CXCL-10, TNF-α, and IL-6 induced by Grampositive and Gram-negative bacterial stimulation. IL-23 and IL-1β were only induced by Gram-negative bacteria. Thus, TLR-2 might be a potential marker and an attractive target for future treatment of patients with SBP. In addition, IL-23 and IL-1β might distinguish early between Gram-positive and Gram-negative SBP.

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Section: Discussionsupporting

confidence: 66%

Kupffer cell activation by different microbial lysates: Toll‐like receptor‐2 plays pivotal role on thromboxane A₂ production in mice and humans

Zhang¹,

Lin²,

Li³

et al. 2020

Eur J Immunol

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“…In order to restore insulin independence after islet transplantation, more than one cadaveric pancreata are usually needed to achieve sufficient islets for one recipient 13 , 14 . One reason is that the inflammation stress during the islet isolation impairs islet viability and function 15 – 18 . The inflammatory signals produced during the isolation procedure can be further amplified through a positive feedback mechanism in the following ex vivo culture period before transplantation, leading to further damage to the islets and affecting transplantation outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…The inflammatory signals produced during the isolation procedure can be further amplified through a positive feedback mechanism in the following ex vivo culture period before transplantation, leading to further damage to the islets and affecting transplantation outcomes. Inhibiting the inflammatory stress during islet isolation is a potential approach to improving islet quality and quantity 15 . In the present study, we identified that CORM-2 effectively reduced the expressions of inflammation factors in the isolated islets, including TF , ICAM-1 , CCL2 , CXCL10 , TLR4 , IL-1β , IL-6 , and TNF-α ( Fig.…”

Section: Discussionmentioning

confidence: 99%

CORM-2 Pretreatment Attenuates Inflammation-mediated Islet Dysfunction

et al. 2020

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During the process of human islet isolation a cascade of stressful events are triggered and negatively influence islet yield, viability, and function, including the production of proinflammatory cytokines and activation of apoptosis. Carbon monoxide-releasing molecule 2 (CORM-2) is a donor of carbon monoxide (CO) and can release CO spontaneously. Accumulating studies suggest that CORM-2 exerts cytoprotective and anti-inflammatory properties. However, the effect of CORM-2 on islet isolation is still unclear. In this study, we found that CORM-2 pretreatment significantly decreased the expression of critical inflammatory genes, including tissue factor, intercellular adhesion molecule-1, chemokine ( C-C motif) ligand 2, C-X-C motif chemokine 10, Toll-like receptor 4, interleukin-1β, interleukin-6, and tumor necrosis factor-α ( TNF-α). The isolated islets of the CORM-2 pretreatment group showed reduced apoptotic rate, improved viability, and higher glucose-stimulated insulin secretion, and functional gene expression in comparison to control group. Importantly, CORM-2 pretreatment prevented the impairment caused by TNF-α, evidenced by the improved glucose-stimulated index and transplantation outcomes. The present study demonstrated the anti-inflammatory property of CORM-2 during human islet isolation, and we suggest that CORM-2 pretreatment is an appealing treatment to mitigate inflammation-mediated islet dysfunction during isolation and culture ex vivo and to preserve long-term islet survival and function.

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“…Islet isolation and transplantation were performed as previously described with minor modifications. 17,18 Briefly, pancreases are perfused with 100-125μg/mL Liberase TL (Roche Diagnostics, Indianapolis, IN) and digested in a 37°C water bath for 18-22 minutes. After washing with HBS the crude digest is purified over a discontinuous density gradient, washed once more with HBS, and cultured overnight in RPMI 1640 (Corning; Corning NY) supplemented with 10% FBS, 10mM HEPES, and 1% penicillin-streptomycin solution.…”

Section: Methodsmentioning

confidence: 99%

Islet transplantation tolerance in animals with defined histocompatibility and diabetes

Bhagchandani

Chang

Zhao

et al. 2021

Preprint

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Advances in organ transplantation benefit from development of genetically inbred animal strains with defined histocompatibility and cell-specific markers to distinguish donor and host cell subsets. For studies of pancreatic islet transplantation tolerance in diabetes, an invariant method to ablate host β cells and induce diabetes would provide an immense additional advantage. Here we detail development and use of B6 RIP-DTR mice , an immunocompetent line permitting diabetes induction with 100% penetrance. This inbred line is homozygous for the C57BL/6J major histocompatibility complex (MHC) haplotype and expresses the mutant CD45.1 allele in the hematopoietic lineage. β cell-specific expression of a high-affinity receptor for diphtheria toxin (DT) permits experimental β cell ablation and diabetes induction after DT administration. Diabetes reversal for over one year was achieved after transplantation with congenic C57BL/6J islets, but not with MHC-mismatched BALB/c islets, which were rapidly rejected. In summary, the generation of a C57BL/6J congenic line harboring the CD45.1 allele and Ins2-HBEGF transgene should advance studies of islet transplantation tolerance and mechanisms to improve islet engraftment and function, thereby optimizing development of cell replacement strategies for diabetes mellitus.

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Early TLR4 Blockade Attenuates Sterile Inflammation-mediated Stress in Islets During Isolation and Promotes Successful Transplant Outcomes

Cited by 15 publications

References 49 publications

Kupffer cell activation by different microbial lysates: Toll‐like receptor‐2 plays pivotal role on thromboxane A₂ production in mice and humans

Kupffer cell activation by different microbial lysates: Toll‐like receptor‐2 plays pivotal role on thromboxane A₂ production in mice and humans

CORM-2 Pretreatment Attenuates Inflammation-mediated Islet Dysfunction

Islet transplantation tolerance in animals with defined histocompatibility and diabetes

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Early TLR4 Blockade Attenuates Sterile Inflammation-mediated Stress in Islets During Isolation and Promotes Successful Transplant Outcomes

Cited by 15 publications

References 49 publications

Kupffer cell activation by different microbial lysates: Toll‐like receptor‐2 plays pivotal role on thromboxane A2 production in mice and humans

Kupffer cell activation by different microbial lysates: Toll‐like receptor‐2 plays pivotal role on thromboxane A2 production in mice and humans

CORM-2 Pretreatment Attenuates Inflammation-mediated Islet Dysfunction

Islet transplantation tolerance in animals with defined histocompatibility and diabetes

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Product

Resources

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Kupffer cell activation by different microbial lysates: Toll‐like receptor‐2 plays pivotal role on thromboxane A₂ production in mice and humans

Kupffer cell activation by different microbial lysates: Toll‐like receptor‐2 plays pivotal role on thromboxane A₂ production in mice and humans