Pharmacological application of carbon monoxide ameliorates islet-directed autoimmunity in mice via anti-inflammatory and anti-apoptotic effects.
OBJECTIVE
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
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.
Department of Immunology, Institute for Biological Research 'Sinisa Stankovic', University of Belgrade, Bul. Despota Stefana 142, 11060, Belgrade, Serbia.
Ivana
I
Nikolic
Tamara
T
Saksida
Katia
K
Mangano
Milica
M
Vujicic
Ivana
I
Stojanovic
Ferdinando
F
Nicoletti
Stanislava
S
Stosic-Grujicic
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D015551:Autoimmunity / Q000276:immunology*; D002248:Carbon Monoxide / Q000008:administration & dosage*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D005260:Female; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018384:Oxidative Stress; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007328:Insulin; D002248:Carbon Monoxide; C505409:Casp3 protein, mouse; D053148:Caspase 3