Pharmacological application of carbon monoxide ameliorates islet-directed autoimmunity in mice via anti-inflammatory and anti-apoptotic effects
2014
Аутори:
Nikolić, IvanaSaksida, Tamara
Mangano, Katia
Vujičić, Milica
Stojanović, Ivana D.
Nicoletti, Ferdinando
Stošić-Grujičić, Stanislava
Тип документа:
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт:
Aims/hypothesis Recent studies have identified carbon monoxide (CO) as a
potential therapeutic molecule for the treatment of autoimmune diseases
owing to its anti-inflammatory and anti-apoptotic properties. We
explored the efficacy and the mechanisms of action of the CO-releasing
molecule (CORM)-A1 in preclinical models of type 1 diabetes.
Methods The impact of CORM-A1 on diabetes development was evaluated in
models of spontaneous diabetes in NOD mice and in diabetes induced in
C57BL/6 mice by multiple low-dose streptozotocin (MLDS). Ex vivo
analysis was performed to determine the impact of CORM-A1 both on T
helper (Th) cell and macrophage differentiation and on their production
of soluble mediators in peripheral tissues and in infiltrates of
pancreatic islets. The potential effect of CORM-A1 on cytokine-induced
apoptosis in pancreatic islets or beta cells was evaluated in vitro.
Results CORM-A1 conferred protection from diabetes in MLDS-induced mice
and reduced diabetes incidence in NOD mice as confirmed by preserved
insulin secretion and improved histological signs of the disease. In
MLDS-challenged mice, CORM-A1 attenuated Th1, Th17, and M1 macrophage
response and facilitated Th2 cell differentiation. In addition, CORM-A1
treatment in NOD mice upregulated the regulatory arm of the immune
response (M2 macrophages and FoxP3(+) regulatory T cells). Importantly,
CORM-A1 interfered with in vitro cytokine-induced beta cell apoptosis
through the reduction of cytochrome c and caspase 3 levels.
Conclusions/interpretation The ability of CORM-A1 to protect mice from
developing type 1 diabetes provides a valuable proof of concept for the
potential exploitation of controlled CO delivery in clinical settings
for the treatment of autoimmune diabetes.
Кључне речи:
Beta cell apoptosis; Carbon monoxide-releasing; molecule-A1; Cytokines; Type 1 diabetesИзвор:
Diabetologia, 2014, 57, 5, 980-990
DOI: 10.1007/s00125-014-3170-7
ISSN: 1432-0428