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1.
Front Mol Biosci ; 9: 895028, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35832733

RESUMEN

Peritonitis and subsequent sepsis lead to high morbidity and mortality in response to uncontrolled systemic inflammation primarily mediated by macrophages. Nicotinamide adenine dinucleotide (NAD+) is an important regulator of oxidative stress and immunoinflammatory responses. However, the effects of NAD+ replenishment during inflammatory activation are still poorly defined. Hence, we investigated whether the administration of ß-nicotinamide mononucleotide (ß-NMN), a natural biosynthetic precursor of NAD+, could modulate the macrophage phenotype and thereby ameliorate the dysregulated inflammatory response during sepsis. For this purpose, C57BL6 mice were subjected to the cecal ligation and puncture (CLP) model to provoke sepsis or were injected with thioglycolate to induce sterile peritonitis with recruitment and differentiation of macrophages into the inflamed peritoneal cavity. ß-NMN was administered for 4 days after CLP and for 3 days post thioglycolate treatment where peritoneal macrophages were subsequently analyzed. In the CLP model, administration of ß-NMN decreased bacterial load in blood and reduced clinical signs of distress and mortality during sepsis. These results were supported by transcriptomic analysis of hearts and lungs 24 h post CLP-induction, which revealed that ß-NMN downregulated genes controlling the immuno-inflammatory response and upregulated genes involved in bioenergetic metabolism, mitochondria, and autophagy. In the thioglycolate model, a significant increase in the proportion of CD206 macrophages, marker of anti-inflammatory M2 phenotype, was detected on peritoneal exudate macrophages from ß-NMN-administered mice. Transcriptomic signature of these macrophages after bacterial stimulation confirmed that ß-NMN administration limited the pro-inflammatory M1 phenotype and induced the expression of specific markers of M2 type macrophages. Furthermore, our data show that ß-NMN treatment significantly impacts NAD + metabolism. This shift in the macrophage phenotype and metabolism was accompanied by a reduction in phagolysosome acidification and secretion of inflammatory mediators in macrophages from ß-NMN-treated mice suggesting a reduced pro-inflammatory activation. In conclusion, administration of ß-NMN prevented clinical deterioration and improved survival during sepsis. These effects relied on shifts in the metabolism of organs that face up an increased energy requirement caused by bacterial infection and in innate immunity response, including reprogramming of macrophages from a highly inflammatory phenotype to an anti-inflammatory/pro-resolving profile.

2.
Cells ; 12(1)2022 12 27.
Artículo en Inglés | MEDLINE | ID: mdl-36611902

RESUMEN

Doxorubicin (Doxo) is a widely used antineoplastic drug with limited clinical application due to its deleterious dose-related side effects. We investigated whether nicotinamide mononucleotide (NMN) could protect against Doxo-induced cardiotoxicity and physical dysfunction in vivo. To assess the short- and long-term toxicity, two Doxo regimens were tested, acute and chronic. In the acute study, C57BL6/J (B6) mice were injected intraperitoneally (i.p.) once with Doxo (20 mg/kg) and NMN (180 mg/kg/day, i.p.) was administered daily for five days before and after the Doxo injection. In the chronic study, B6 mice received a cumulative dose of 20 mg/kg Doxo administered in fractionated doses for five days. NMN (500 mg/kg/day) was supplied in the mice's drinking water beginning five days before the first injection of Doxo and continuing for 60 days after. We found that NMN significantly increased tissue levels of NAD+ and its metabolites and improved survival and bodyweight loss in both experimental models. In addition, NMN protected against Doxo-induced cardiotoxicity and loss of physical function in acute and chronic studies, respectively. In the heart, NMN prevented Doxo-induced transcriptomic changes related to mitochondrial function, apoptosis, oxidative stress, inflammation and p53, and promyelocytic leukemia nuclear body pathways. Overall, our results suggest that NMN could prevent Doxo-induced toxicity in heart and skeletal muscle.


Asunto(s)
Cardiotoxicidad , Mononucleótido de Nicotinamida , Ratones , Animales , Cardiotoxicidad/prevención & control , Mononucleótido de Nicotinamida/farmacología , Doxorrubicina/toxicidad , Corazón , Apoptosis
3.
Food Chem Toxicol ; 150: 112060, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33587977

RESUMEN

ß-nicotinamide mononucleotide (NMN) is a natural molecule intermediate in the biosynthesis of nicotinamide adenine dinucleotide (NAD+). Preclinical evidences point to the beneficial effect of NMN administration on several age-related conditions. The present work aimed at studying mutagenicity, and genotoxicity, acute oral toxicity and subchronic oral toxicity of a high purity synthetic form of NMN (NMN-C®) following the OECD guidelines. In the experimental conditions tested, NMN-C® was not mutagenic or genotoxic. Acute toxicity assay revealed that at an oral limit dose of 2666 mg/kg, NMN-C® did not lead to any mortality or treatment-related adverse signs. Over a 90-day sub-chronic period of repeated oral administration of NMN-C® at doses of 375, 750 and 1500 mg/kg/d followed by a 28-day treatment-free recovery period, NMN-C® appeared to be safe and did not promote toxic effects as seen from body weight change, food and water consumption, feed conversion efficiency, biochemical and blood parameters as well as organ toxicity and histological examinations of main organs. In conclusion, we provide the first data highlighting the safety of short to intermediate term (sub-chronic) oral administration of NMN and our experimental results allowed to determine a No-Observable Adverse Effect Level (NOAEL) for NMN-C® to be ≥ 1500 mg/kg/d.


Asunto(s)
Mononucleótido de Nicotinamida/toxicidad , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Masculino , Estructura Molecular , Mononucleótido de Nicotinamida/administración & dosificación , Mononucleótido de Nicotinamida/química , Ratas , Ratas Sprague-Dawley , Pruebas de Toxicidad
4.
Eur J Immunol ; 51(1): 76-90, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32700362

RESUMEN

Upon viral infection, stressed or damaged cells can release alarmins like IL-33 that act as endogenous danger signals alerting innate and adaptive immune cells. IL-33 coming from nonhematopoietic cells has been identified as important factor triggering the expansion of antiviral CD8+ T cells. In LN the critical cellular source of IL-33 is unknown, as is its potential cell-intrinsic function as a chromatin-associated factor. Using IL-33-GFP reporter mice, we identify fibroblastic reticular cells (FRC) and lymphatic endothelial cells (LEC) as the main IL-33 source. In homeostasis, IL-33 is dispensable as a transcriptional regulator in FRC, indicating it functions mainly as released cytokine. Early during infection with lymphocytic choriomeningitis virus (LCMV) clone 13, both FRC and LEC lose IL-33 protein expression suggesting cytokine release, correlating timewise with IL-33 receptor expression by reactive CD8+ T cells and their greatly augmented expansion in WT versus ll33-/- mice. Using mice lacking IL-33 selectively in FRC versus LEC, we identify FRC as key IL-33 source driving acute and chronic antiviral T-cell responses. Collectively, these findings show that LN T-zone FRC not only regulate the homeostasis of naïve T cells but also their expansion and differentiation several days into an antiviral response.


Asunto(s)
Interleucina-33/metabolismo , Coriomeningitis Linfocítica/inmunología , Enfermedad Aguda , Inmunidad Adaptativa , Animales , Linfocitos T CD8-positivos/inmunología , Enfermedad Crónica , Células Endoteliales/inmunología , Fibroblastos/inmunología , Homeostasis , Humanos , Inmunidad Innata , Interleucina-33/deficiencia , Interleucina-33/genética , Ganglios Linfáticos/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Modelos Inmunológicos
5.
PLoS Biol ; 17(7): e3000072, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31306410

RESUMEN

Lymphoid T-zone fibroblastic reticular cells (FRCs) actively promote T-cell trafficking, homeostasis, and expansion but can also attenuate excessive T-cell responses via inducible nitric oxide (NO) and constitutive prostanoid release. It remains unclear how these FRC-derived mediators dampen T-cell responses and whether this occurs in vivo. Here, we confirm that murine lymph node (LN) FRCs produce prostaglandin E2 (PGE2) in a cyclooxygenase-2 (COX2)-dependent and inflammation-independent fashion. We show that this COX2/PGE2 pathway is active during both strong and weak T-cell responses, in contrast to NO, which only comes into play during strong T-cell responses. During chronic infections in vivo, PGE2-receptor signaling in virus-specific cluster of differentiation (CD)8 cytotoxic T cells was shown by others to suppress T-cell survival and function. Using COX2flox/flox mice crossed to mice expressing Cre recombinase expression under control of the CC chemokine ligand (CCL19) promoter (CCL19cre), we now identify CCL19+ FRC as the critical source of this COX2-dependent suppressive factor, suggesting PGE2-expressing FRCs within lymphoid tissues are an interesting therapeutic target to improve T-cell-mediated pathogen control during chronic infection.


Asunto(s)
Ciclooxigenasa 2/inmunología , Fibroblastos/inmunología , Ganglios Linfáticos/inmunología , Prostaglandinas/inmunología , Linfocitos T/inmunología , Animales , Línea Celular , Movimiento Celular/genética , Movimiento Celular/inmunología , Proliferación Celular/genética , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Fibroblastos/metabolismo , Fibroblastos/virología , Ganglios Linfáticos/citología , Ganglios Linfáticos/metabolismo , Activación de Linfocitos/inmunología , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/metabolismo , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Prostaglandinas/biosíntesis , Linfocitos T/virología
6.
Proc Natl Acad Sci U S A ; 115(29): E6826-E6835, 2018 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-29967180

RESUMEN

Antibody-secreting plasma cells (PCs) arise rapidly during adaptive immunity to control infections. The early PCs are retained within the reactive lymphoid organ where their localization and homeostasis rely on extrinsic factors, presumably produced by local niche cells. While myeloid cells have been proposed to form those niches, the contribution by colocalizing stromal cells has remained unclear. Here, we characterized a subset of fibroblastic reticular cells (FRCs) that forms a dense meshwork throughout medullary cords of lymph nodes (LNs) where PCs reside. This medullary FRC type is shown to be anatomically, phenotypically, and functionally distinct from T zone FRCs, both in mice and humans. By using static and dynamic imaging approaches, we provide evidence that medullary FRCs are the main cell type in contact with PCs guiding them in their migration. Medullary FRCs also represent a major local source of the PC survival factors IL-6, BAFF, and CXCL12, besides also producing APRIL. In vitro, medullary FRCs alone or in combination with macrophages promote PC survival while other LN cell types do not have this property. Thus, we propose that this FRC subset, together with medullary macrophages, forms PC survival niches within the LN medulla, and thereby helps in promoting the rapid development of humoral immunity, which is critical in limiting early pathogen spread.


Asunto(s)
Formación de Anticuerpos , Homeostasis/inmunología , Ganglios Linfáticos/inmunología , Células Plasmáticas/inmunología , Animales , Factor Activador de Células B/inmunología , Quimiocina CXCL12/inmunología , Interleucina-6/inmunología , Ganglios Linfáticos/citología , Masculino , Ratones , Células Plasmáticas/citología , Células del Estroma/citología , Células del Estroma/inmunología
7.
J Med Chem ; 60(23): 9617-9629, 2017 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-29111717

RESUMEN

Tumors use tryptophan-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of a key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology. Starting from HTS hit 5, IDO-1 inhibitor 6 (EOS200271/PF-06840003) has been developed. The structure-activity relationship around 6 is described and rationalized using the X-ray crystal structure of 6 bound to human IDO-1, which shows that 6, differently from most of the IDO-1 inhibitors described so far, does not bind to the heme iron atom and has a novel binding mode. Clinical candidate 6 shows good potency in an IDO-1 human whole blood assay and also shows a very favorable ADME profile leading to favorable predicted human pharmacokinetic properties, including a predicted half-life of 16-19 h.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indoles/farmacología , Succinimidas/farmacología , Animales , Línea Celular , Cristalografía por Rayos X , Perros , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/química , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indoles/química , Indoles/farmacocinética , Macaca fascicularis , Masculino , Ratones , Simulación del Acoplamiento Molecular , Ratas , Relación Estructura-Actividad , Succinimidas/química , Succinimidas/farmacocinética
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