Nitric oxide, chronic inflammation and autoimmunity

Nagy, György; Clark, Joanna M.; Buzás, Edit I.; Gorman, Claire; Cope, Andrew P.

doi:10.1016/j.imlet.2007.04.013

Cited by 149 publications

(111 citation statements)

References 37 publications

Supporting

Mentioning

105

Contrasting

Unclassified

Order By: Relevance

“…Macrophages are a main source of proinflammatory cytokines and NO. Experiments with mice deficient in IL-1or IL-1 receptor antagonist, as well as the inhibition of NO synthesis, have demonstrated their role in inflammatory or autoimmune diseases such as lupus or rheumatoid arthritis (41,42), and further studies on UCP2 in these pathologies would be instructive. Indeed, in humans, high levels of UCP2 were associated with reduced susceptibility to multiple sclerosis (43) and reduced risk of diabetic neuropathy in type 1 diabetes (44).…”

Section: Discussionmentioning

confidence: 99%

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

Emre

Hurtaud

Karaca

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

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....

show abstract

Section: Discussionmentioning

confidence: 99%

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

Emre

Hurtaud

Karaca

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…It plays a critical role in regulation of vascular blood pressure (4), lung airway relaxation (5), and immune response (6). In heterodimeric sGC, the GTP catalytic site is located presumably at the interface between both subunits, whereas the sensing domain in ␤-subunit contains the heme group necessary for NO binding.…”

Section: ؊1 ⅐Smentioning

confidence: 99%

Quaternary Structure Controls Ligand Dynamics in Soluble Guanylate Cyclase

Yoo

Lamarre

Martin

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: NO and CO dynamics are compared in soluble guanylate cyclase and isolated heme domain. Results: CO geminately rebinds to the isolated heme domain ␤ 1 (190), contrary to entire sGC. Photo-oxidation of ␤ 1 (190) heme may occur. Conclusion:The isolated heme domain ␤ 1 (190) has a different reactivity than full-length sGC. Significance: The structural strains between domains in the full-length protein are crucial for its functioning.

show abstract

“…The diatomic messenger NO and sGC play a critical role in several physiological processes: regulation of vascular blood pressure and cardiovascular diseases (3), lung airway relaxation and pulmonary pathologies (4), immune response and inflammatory disorders (5), and tumor progression and apoptosis (6). Thus, sGC is a pharmacological target of very high interest, and several activators have been developed (7,8), leading to the approval of riociguat for the treatment of pulmonary hypertension (9,10).…”

mentioning

confidence: 99%

Motion of proximal histidine and structural allosteric transition in soluble guanylate cyclase

Yoo

Lamarre

Martin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

We investigated the changes of heme coordination in purified soluble guanylate cyclase (sGC) by time-resolved spectroscopy in a time range encompassing 11 orders of magnitude (from 1 ps to 0.2 s). After dissociation, NO either recombines geminately to the 4-coordinate (4c) heme (τ G1 = 7.5 ps; 97 ± 1% of the population) or exits the heme pocket (3 ± 1%). The proximal His rebinds to the 4c heme with a 70-ps time constant. Then, NO is distributed in two approximately equal populations (1.5%). One geminately rebinds to the 5c heme (τ G2 = 6.5 ns), whereas the other diffuses out to the solution, from where it rebinds bimolecularly (τ = 50 μs with [NO] = 200 μM) forming a 6c heme with a diffusion-limited rate constant of 2 × 10 8 M −1 ·s −1 . In both cases, the rebinding of NO induces the cleavage of the Fe-His bond that can be observed as an individual reaction step. Saliently, the time constant of bond cleavage differs depending on whether NO binds geminately or from solution (τ 5C1 = 0.66 μs and τ 5C2 = 10 ms, respectively). Because the same event occurs with rates separated by four orders of magnitude, this measurement implies that sGC is in different structural states in both cases, having different strain exerted on the Fe-His bond. We show here that this structural allosteric transition takes place in the range 1-50 μs. In this context, the detection of NO binding to the proximal side of sGC heme is discussed.soluble guanylate cyclase | nitric oxide | time-resolved absorption spectroscopy | allostery | protein activation T he soluble guanylate cyclase (sGC), localized in many different cell types, is the receptor of the endogenous messenger nitric oxide (NO) and catalyzes the formation of cGMP from GTP upon activation triggered by NO binding (1, 2). The diatomic messenger NO and sGC play a critical role in several physiological processes: regulation of vascular blood pressure and cardiovascular diseases (3), lung airway relaxation and pulmonary pathologies (4), immune response and inflammatory disorders (5), and tumor progression and apoptosis (6). Thus, sGC is a pharmacological target of very high interest, and several activators have been developed (7,8), leading to the approval of riociguat for the treatment of pulmonary hypertension (9, 10). Because of its pharmacological interest, the mechanisms of activation, deactivation, and regulation of sGC must be deciphered at the molecular level. Despite numerous efforts, the 3D crystal structure of heterodimeric sGC remains unknown, but the heme domain of the sGC β1-subunit [called heme NO/oxygen-binding (H-NOX)] was modeled from the heme domain of bacterial NO sensors (11,12) and the sGC catalytic α1-subunit was modeled from the catalytic α1-subunit of adenylate cyclase (13). Recently, the entire quaternary structure of sGC was reconstructed by inserting individual protein domains into the density envelope of entire single-sGC molecules observed by EM (14), revealing a high flexibility of the sGC dimer. Subsequently, the structural perturbations induced by NO bi...

show abstract

Nitric oxide, chronic inflammation and autoimmunity

Cited by 149 publications

References 37 publications

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

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

Quaternary Structure Controls Ligand Dynamics in Soluble Guanylate Cyclase

Motion of proximal histidine and structural allosteric transition in soluble guanylate cyclase

Contact Info

Product

Resources

About