Role of uncoupling protein UCP2 in cell-mediated immunity: How macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes

Abstract

Infiltration of inflammatory cells into pancreatic islets of Langerhans and selective destruction of insulin-secreting ␤-cells are characteristics of type 1 diabetes. Uncoupling protein 2 (UCP2) is a mitochondrial protein expressed in immune cells. UCP2 controls macrophage activation by modulating the production of mitochondrial reactive oxygen species (ROS) and MAPK signaling. We investigated the role of UCP2 on immune cell activity in type 1 diabetes in Ucp2-deficient mice. Using the model of multiple low-dose streptozotocin (STZ)-induced diabetes, we found that autoimmune diabetes was strongly accelerated in Ucp2-KO mice, compared with Ucp2-WT mice with increased intraislet lymphocytic infiltration. Macrophages from STZ-treated Ucp2-KO mice had increased IL-1␤ and nitric oxide (NO) production, compared with WT macrophages. Moreover, more macrophages were recruited in islets of STZ-treated Ucp2-KO mice, compared with Ucp2-WT mice. This finding also was accompanied by increased NO/ROS-induced damage. Altogether, our data show that inflammation is stronger in Ucp2-KO mice and islets, leading to the exacerbated disease in these mice. Our results highlight the mitochondrial protein UCP2 as a new player in autoimmune diabetes.inflammation ͉ nitric oxide M itochondria are important organelles for cellular functions, including ATP synthesis. Oxidative glucose metabolism in pancreatic ␤-cells increases the ATP/ADP ratio, leading to insulin release. Uncoupling protein 2 (UCP2) is a mitochondrial carrier protein expressed in pancreatic ␤-cells (1, 2) and immune cells (3,4).In pancreatic ␤-cells, UCP2 was reported to alter the yield of ATP synthesis from glucose, and it has been proposed as a negative regulator of glucose-stimulated insulin secretion (2). In other respects, there is much evidence for the influence of UCP2 on immune responses. First, Ucp2-KO mice exhibit increased resistance to a Toxoplasma gondii or Listeria monocytogenes infection (4, 5). Second, in an LDL receptor-null background, Ucp2-KO mice develop greater and more unstable atherosclerotic plaques than WT mice (6). Third, in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis, Ucp2-KO mice develop higher disease scores than Ucp2-WT mice (7). We showed that UCP2 regulates LPS-induced reactive oxygen species (ROS) signaling in macrophages (8). MAPK activation in Ucp2-KO macrophages is quicker and stronger than in WT macrophages (8), leading to increased nitric oxide (NO), cytokine production, and migration ability (8, 9). Consistent with these findings, overexpression of UCP2 in macrophages is associated with diminished NO production (10) and decreased migration capacity (11).Given the evidence for a role of UCP2 in the immune system, in macrophages, and in ␤-cell function, we investigated whether UCP2 affects the development of autoimmune diabetes by using the model of multiple low-dose of streptozotocin (STZ). In this report, we show that the absence of UCP2 renders animals more sensitive to the onset of diabetes in mice....

UCP2, a metabolic sensor coupling glucose oxidation to mitochondrial metabolism?

“…Furthermore, Ucp22/2 mice or irradiated LDL-R-deficient mice transplanted with bone marrow from Ucp22/2 mice displayed bigger and more unstable atherosclerotic plaques when fed on a high fat diet than control mice (24,25). Consistent with a role for Ucp2 in autoimmune-mediated disease, induction of type I diabetes by injection of low-dose streptozotocin occurred faster in Ucp22/2 mice compared to wild-type controls (26). Finally, Ucp22/2 mice are protected against cerebral ischemia following middle cerebral artery occlusion (27), whereas overexpression of UCP2 in the brain prevents seizure or stroke by decreasing neuronal death (28,29).…”

Mitochondrial uncoupling protein 2 in pancreatic β‐cells

“…They may be further complicated by secondary or systemic effects caused by the global and chronic lack of a particular protein. Inconsistency in the effect of Ucp2 ablation on glucose tolerance and GSIS in mice, for example, may be partly because of the loss of UCP2 in other cell types, such as macrophages (affecting immune status [29]) and POMC neurons (affecting the response to glucose [25]). Such effects can be avoided by studying UCP2 function in a model system such as cultured insulinoma cells, for example INS-1E cells, that have been specifically selected to retain important mechanistic characteristics of primary β-cells, including prominent GSIS [30]…”

A carbon monoxide-releasing molecule (CORM-3) uncouples mitochondrial respiration and modulates the production of reactive oxygen species

“…Mitochondrial uncoupling essentially drives an energy-dissipating proton cycle across the mitochondrial inner membrane resulting in a compensatory increase in O 2 consumption that is not accompanied by production of ATP [19]. This can be achieved through various mechanisms including activation of adenine nucleotide transporters (ANT) and uncoupling proteins (UCPs), which have been shown to be crucial for cell survival and homeostasis in various disease states [20][21][22][23][24]. Here we report that low micromolar concentrations of CO, delivered to isolated heart mitochondria by a water-soluble CO-RM, uncouple mitochondrial respiration consequently modulating both ROS production and bioenergetic parameters.…”