CORM-2 Pretreatment Attenuates Inflammation-mediated Islet Dysfunction

Abstract

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.

The inhibition of FKBP5 protects β-cell survival under inflammation stress via AKT/FOXO1 signaling

“…Here, we firstly demonstrated that FKBP5 inhibition by siRNAs or inhibitor SAFit2 activates the autophagy flux in inflammation cytokines treated β cells, which may facilitate β-cell survival under inflammation stress. In addition, inflammation is also a common stress for islet isolation [ 30 ]. In the ex vivo-cultured human islets and mice islets, we found that FKBP5 inhibition improved β-cell function, evidenced by the increased expression of β-cell functional genes NKX6.1 and PDX1 and by the enhanced glucose-stimulated insulin secretion, confirming the protective effect of FKBP5 in β cells.…”

The inhibition of FKBP5 protects β cell survival under inflammation stress via AKT/FOXO1 signaling.

“…Here, we rstly demonstrated that FKBP5 inhibition by siRNAs or inhibitor SAFit2 activates the autophagy ux in in ammation cytokines treated β cells, which may facilitate β cell survival under in ammation stress. In addition, in ammation is also a common stress for islet isolation [31] . In the ex vivo cultured human islets and mice islets, we found that FKBP5 inhibition improved β cell function, evidenced by the increased expression of β cell functional genes NKX6.1 and PDX1 and by the enhanced glucose stimulated insulin secretion, con rming the protective effect of FKBP5 in β cells.…”

Carbon Monoxide in Pancreatic Islet Transplantation: A New Therapeutic Alternative to Patients With Severe Type 1 Diabetes Mellitus

“…In furtherance of the use of CO gas in pancreatic islet transplantation, a very recent study shows that CO-RMs can produce the same salutary effects as CO gas. Pretreatment with 100 μM CORM-2 during islet isolation and subsequently transplanted (150 in number) into renal subcapsular space of STZ (165 mg/kg)-induced type 1 diabetic recipient mice resulted in significant downregulation of the expression of important proinflammatory genes such as TNF-α, interleukin-1beta (IL-1β), IL-6, intercellular adhesion molecule-1 (ICAM-1), Toll-like receptor 4 (TLR4), tissue factor (TF), chemokine ligand 2 (CCL2) and C-X-C motif ligand 10 (CXCL10) (Figure 1), which strongly correlated with markedly reduced apoptosis, improved islet cell viability, and higher glucose-stimulated insulin secretion and transplantation outcomes in comparison with control group (Cai et al, 2020). These findings suggest that treatment of islet grafts with CORM-2 at the beginning of isolation has the potential to protect the grafts in recipients from innate inflammation and apoptosis (two important factors that account for the progressive loss of islet function after transplantation in clinical practice) from the beginning of islet harvest through peri-transplant to post-transplant periods and could improve the quality and quantity of isolated human islets.…”

“…There is also non-metallic CO-RMs such as CORM-A1 (Motterlini et al, 2005b). Burgeoning evidence from preclinical studies shows that administration of CO-RMs during pancreatic islet isolation increases islet yields and insulin independence in type 1 diabetic transplant recipients (Nikolic et al, 2014;Nikolic et al, 2015;Cai et al, 2020). This minireview discusses current knowledge of CO gas and CO-RMs in preclinical pancreatic islet transplantation and underlying molecular mechanisms that ensure islet protection during isolation, islet culture, transplantation and post-transplant periods.…”