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1.
Results Probl Cell Differ ; 74: 341-364, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39406913

RESUMEN

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) was first identified in 1882 by Robert Koch, and it is estimated that this pathogen has been around for as long as 3 million years.The World Health Organization (WHO) reported that in 2022 alone an estimated 10.6 million people developed TB worldwide, making TB the world's second leading cause of death from a single infectious agent, just after coronavirus disease (COVID-19), despite TB being a preventable and usually curable disease.Moreover, epidemiological studies suggest that approximately a quarter of the global population has been infected with TB bacteria, of which 5-10% will eventually develop symptoms and TB disease. Poverty, obesity, diabetes, and alcohol use contribute to the burden of TB.Alveolar macrophages play a pivotal role in the clearance of airborne pathogenic microorganisms and are the primary target of M. tuberculosis.Macrophage activity depend on metabolism and circadian rhythmicity, and mitochondria are a central hub that coordinates the communication between metabolism, circadian rhythmicity, and the immune system.Recent evidence has thrown light on how M. tuberculosis metabolism may regulate macrophage activity and the overall host responses to M. tuberculosis infection.This chapter explores how all these biological domains relate to each other, highlighting the multidimensional nature of TB, and positioning macrophages at center stage.


Asunto(s)
Ritmo Circadiano , Macrófagos , Mitocondrias , Mycobacterium tuberculosis , Tuberculosis , Humanos , Tuberculosis/inmunología , Ritmo Circadiano/fisiología , Mitocondrias/metabolismo , Macrófagos/microbiología , Macrófagos/metabolismo , Macrófagos/inmunología , Animales
2.
Eur J Med Res ; 29(1): 497, 2024 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-39407333

RESUMEN

Type 2 diabetes (T2D) is associated with insulin resistance and progressive dysfunction of ß-pancreatic cells, leading to persistent hyperglycemia. Macrophages play a crucial role in this context, influencing both the development and progression of insulin resistance. These innate immune cells respond to inflammatory stimuli and reprogram their metabolism, directly impacting the pathophysiology of T2D. Macrophages are highly plastic and can adopt either pro-inflammatory or pro-resolutive phenotypic profiles. In T2D, pro-inflammatory macrophages, which rely on glycolysis, exacerbate insulin resistance through increased production of pro-inflammatory cytokines and nitric oxide. In contrast, pro-resolutive macrophages, which prioritize fatty acid metabolism, have different effects on glucose homeostasis. Metaflammation, a chronic low-grade inflammation, is induced by pro-inflammatory macrophages and significantly contributes to the progression of T2D, creating an environment conducive to metabolic dysfunction. This review aims to clarify the contribution of macrophages to the progression of T2D by detailing how their inflammatory responses and metabolic reprogramming influence insulin resistance and the disease's pathophysiology. The review seeks to deepen the understanding of the biochemical and metabolic mechanisms involved, offering broader insights into the impact on the quality of life for millions of patients worldwide.


Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Macrófagos , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Macrófagos/metabolismo , Macrófagos/inmunología , Inflamación/metabolismo , Animales , Reprogramación Celular , Reprogramación Metabólica
3.
Int J Mol Sci ; 25(19)2024 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-39408569

RESUMEN

Obesity causes insulin resistance (IR) through systemic low-grade inflammation and can lead to type 2 diabetes mellitus (T2DM). However, the mechanisms that cause IR and T2DM in non-obese individuals are unclear. The Goto-Kakizaki (GK) rat develops IR spontaneously and is a model of non-obese T2DM. These rats exhibit hyperglycemia beginning at weaning and exhibit lower body mass than control Wistar rats. Herein, we tested the hypothesis that macrophages of GK rats are permanently in a pro-inflammatory state, which may be associated with a systemic inflammation condition that mimics the pathogenesis of obesity-induced T2DM. Using eighteen-week-old GK and control Wistar rats, we investigated the proportions of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages isolated from the peritoneal cavity. Additionally, the production of inflammatory cytokines and reactive oxygen species (ROS) in cultured macrophages under basal and stimulated conditions was assessed. It was found that phorbol myristate acetate (PMA) stimulation increased GK rat macrophage ROS production 90-fold compared to basal levels. This response was also three times more pronounced than in control cells (36-fold). The production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), tended to be upregulated in cultured macrophages from GK rats under basal conditions. Macrophages from GK rats produced 1.6 times more granulocyte-macrophage colony-stimulating factor (GM-CSF), 1.5 times more monocyte chemoattractant protein-1 (MCP-1) and 3.3 times more TNF-α than control cells when stimulated with lipopolysaccharide (LPS) (p = 0.0033; p = 0.049; p = 0.002, respectively). Moreover, compared to control cells, GK rats had 60% more M1 (p = 0.0008) and 23% less M2 (p = 0.038) macrophages. This study is the first to report macrophage inflammatory reprogramming towards a pro-inflammatory state in GK rats.


Asunto(s)
Diabetes Mellitus Tipo 2 , Inflamación , Macrófagos , Ratas Wistar , Especies Reactivas de Oxígeno , Animales , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/inmunología , Ratas , Macrófagos/metabolismo , Macrófagos/inmunología , Especies Reactivas de Oxígeno/metabolismo , Inflamación/patología , Inflamación/metabolismo , Masculino , Citocinas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Modelos Animales de Enfermedad , Resistencia a la Insulina
4.
Cells ; 13(18)2024 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-39329752

RESUMEN

Cardiotonic steroids are known to bind to Na+/K+-ATPase and regulate several biological processes, including the immune response. The synthetic cardiotonic steroid γ-Benzylidene Digoxin 8 (BD-8) is emerging as a promising immunomodulatory molecule, although it has remained largely unexplored. Therefore, we tested the immunomodulatory potential of BD-8 both in vitro and in vivo. Hence, primary mouse macrophages were incubated with combinations of BD-8 and the pro-inflammatory fungal protein zymosan (ZYM). Nitric oxide (NO) production was determined by Griess reagent and cytokines production was assessed by enzyme-linked immunosorbent assay. Inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), p-nuclear factor kappa B p65 (NF-κB p65), p-extracellular signal-regulated kinase (p-ERK), and p-p38 were evaluated by flow cytometry. Macrophages exposed to BD-8 displayed reduced phagocytic activity, NO levels, and production of the proinflammatory cytokine IL-1ß induced by ZYM. Furthermore, BD-8 diminished the expression of iNOS and phosphorylation of NF-κB p65, ERK, and p38. Additionally, BD-8 exhibited anti-inflammatory capacity in vivo in a carrageenan-induced mouse paw edema model. Taken together, these findings demonstrate the anti-inflammatory activity of BD-8 and further reinforce the potential of cardiotonic steroids and their derivatives as immunomodulatory molecules.


Asunto(s)
Antiinflamatorios , Digoxina , Macrófagos , Animales , Ratones , Antiinflamatorios/farmacología , Digoxina/farmacología , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico/metabolismo , Masculino , Citocinas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Cardiotónicos/farmacología , Factor de Transcripción ReIA/metabolismo , Interleucina-1beta/metabolismo , Zimosan , Edema/tratamiento farmacológico , Edema/patología , Inflamación/tratamiento farmacológico , Inflamación/patología
5.
Biol Res ; 57(1): 64, 2024 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-39252136

RESUMEN

BACKGROUND: Testicular macrophages (TM) have long been recognized for their role in immune response within the testicular environment. However, their involvement in steroid hormone synthesis, particularly testosterone, has not been fully elucidated. This study aims to explore the capability of TM to synthesize and secrete testosterone de novo and to investigate the regulatory mechanisms involved. RESULTS: Transcriptomic analysis revealed significant expression of Cyp11a1, Cyp17a1, Hsd3b1, and Hsd17b3 in TM, which are key enzymes in the testosterone synthesis pathway. qPCR analysis and immunofluorescence validation confirmed the autonomous capability of TM to synthesize testosterone. Ablation of TM in mice resulted in decreased physiological testosterone levels, underscoring the significance of TM in maintaining testicular testosterone levels. Additionally, the study also demonstrated that Cebpb regulates the expression of these crucial genes, thereby modulating testosterone synthesis. CONCLUSIONS: This research establishes that TM possess the autonomous capacity to synthesize and secrete testosterone, contributing significantly to testicular testosterone levels. The transcription factor Cebpb plays a crucial role in this process by regulating the expression of key genes involved in testosterone synthesis.


Asunto(s)
Proteína beta Potenciadora de Unión a CCAAT , Macrófagos , Testículo , Testosterona , Animales , Masculino , Testosterona/metabolismo , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Testículo/metabolismo , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Perfilación de la Expresión Génica
6.
Photochem Photobiol Sci ; 23(9): 1735-1747, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39227554

RESUMEN

The mdx mouse phenotype, aggravated by chronic exercise on a treadmill, makes this murine model more reliable for the study of Duchenne muscular dystrophy (DMD) and allows the efficacy of therapeutic interventions to be evaluated. This study aims to investigate the effects of photobiomodulation by light-emitting diode (LED) therapy on functional, biochemical and morphological parameters in treadmill-trained adult mdx animals. Mdx mice were trained for 30 min of treadmill running at a speed of 12 m/min, twice a week for 4 weeks. The LED therapy (850 nm) was applied twice a week to the quadriceps muscle throughout the treadmill running period. LED therapy improved behavioral activity (open field) and muscle function (grip strength and four limb hanging test). Functional benefits correlated with reduced muscle damage; a decrease in the inflammatory process; modulation of the regenerative muscular process and calcium signalling pathways; and a decrease in oxidative stress markers. The striking finding of this work is that LED therapy leads to a shift from the M1 to M2 macrophage phenotype in the treadmill-trained mdx mice, enhancing tissue repair and mitigating the dystrophic features. Our data also imply that the beneficial effects of LED therapy in the dystrophic muscle correlate with the interplay between calcium, oxidative stress and inflammation signalling pathways. Together, these results suggest that photobiomodulation could be a potential adjuvant therapy for dystrophinopathies.


Asunto(s)
Macrófagos , Ratones Endogámicos mdx , Distrofia Muscular de Duchenne , Fenotipo , Animales , Ratones , Macrófagos/metabolismo , Distrofia Muscular de Duchenne/terapia , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología , Condicionamiento Físico Animal , Masculino , Estrés Oxidativo , Modelos Animales de Enfermedad , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Luz
7.
Front Immunol ; 15: 1462853, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39346907

RESUMEN

Macrophages play a pivotal role in tissue homeostasis, pathogen defense, and inflammation resolution. M1 and M2 macrophage phenotypes represent two faces in a spectrum of responses to microenvironmental changes, crucial in both physiological and pathological conditions. Neuraminidase 1 (Neu1), a lysosomal and cell surface sialidase responsible for removing terminal sialic acid residues from glycoconjugates, modulates several macrophage functions, including phagocytosis and Toll-like receptor (TLR) signaling. Current evidence suggests that Neu1 expression influences M1/M2 macrophage phenotype alterations in the context of cardiovascular diseases, indicating a potential role for Neu1 in macrophage polarization. For this reason, we investigated the impact of Neu1 deficiency on macrophage polarization in vitro and in vivo. Using bone marrow-derived macrophages (BMDMs) and peritoneal macrophages from Neu1 knockout (Neu1-/- ) mice and wild-type (WT) littermate controls, we demonstrated that Neu1-deficient macrophages exhibit an aberrant M2-like phenotype, characterized by elevated macrophage mannose receptor 1 (MMR/CD206) expression and reduced responsiveness to M1 stimuli. This M2-like phenotype was also observed in vivo in peritoneal and splenic macrophages. However, lymph node (LN) macrophages from Neu1-/- mice exhibited phenotypic alterations with reduced CD206 expression. Further analysis revealed that peripheral LNs from Neu1-/- mice were highly fibrotic, with overexpression of transforming growth factor-beta 1 (TGF-ß1) and hyperactivated TGF-ß signaling in LN macrophages. Consistently, TGF-ß1 was found to alter M1/M2 macrophage polarization in vitro. Our findings showed that Neu1 deficiency prompts macrophages towards an M2 phenotype and that microenvironmental changes, particularly increased TGF-ß1 in fibrotic tissues such as peripheral LNs in Neu1-/- mice, further influence M1/M2 macrophage polarization, highlighting its sensitivity to the local microenvironment. Therapeutic interventions targeting Neu1 or TGF-ß signaling pathways may offer the potential to regulate macrophage behavior across different diseases.


Asunto(s)
Microambiente Celular , Fibrosis , Ganglios Linfáticos , Macrófagos , Ratones Noqueados , Neuraminidasa , Animales , Ratones , Macrófagos/inmunología , Macrófagos/metabolismo , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Neuraminidasa/deficiencia , Neuraminidasa/genética , Neuraminidasa/metabolismo , Ratones Endogámicos C57BL , Activación de Macrófagos , Lectinas Tipo C/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/deficiencia , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Células Cultivadas , Transducción de Señal , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Receptores de Superficie Celular/deficiencia , Receptor de Manosa , Fenotipo , Factor de Crecimiento Transformador beta1/metabolismo
8.
Chem Biol Interact ; 403: 111216, 2024 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-39218371

RESUMEN

Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania and is responsible for more than 1 million new cases and 70,000 deaths annually worldwide. Treatment has high costs, toxicity, complex and long administration time, several adverse effects, and drug-resistant strains, therefore new therapies are urgently needed. Synthetic compounds have been highlighted in the medicinal chemistry field as a strong option for drug development against different diseases. Organic salts (OS) have multiple biological activities, including activity against protozoa such as Leishmania spp. This study aimed to investigate the in vitro leishmanicidal activity and death mechanisms of a thiohydantoin salt derived from l-arginine (ThS) against Leishmania amazonensis. We observed that ThS treatment inhibited promastigote proliferation, increased ROS production, phosphatidylserine exposure and plasma membrane permeabilization, loss of mitochondrial membrane potential, lipid body accumulation, autophagic vacuole formation, cell cycle alteration, and morphological and ultrastructural changes, showing parasites death. Additionally, ThS presents low cytotoxicity in murine macrophages (J774A.1), human monocytes (THP-1), and sheep erythrocytes. ThS in vitro cell treatment reduced the percentage of infected macrophages and the number of amastigotes per macrophage by increasing ROS production and reducing TNF-α levels. These results highlight the potential of ThS among thiohydantoins, mainly related to the arginine portion, as a leishmanicidal drug for future drug strategies for leishmaniasis treatment. Notably, in silico investigation of key targets from L. amazonensis, revealed that a ThS compound from the l-arginine amino acid strongly interacts with arginase (ARG) and TNF-α converting enzyme (TACE), suggesting its potential as a Leishmania inhibitor.


Asunto(s)
Arginina , Leishmania , Macrófagos , Simulación del Acoplamiento Molecular , Especies Reactivas de Oxígeno , Animales , Arginina/farmacología , Arginina/química , Arginina/metabolismo , Ratones , Humanos , Leishmania/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/parasitología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ovinos , Antiprotozoarios/farmacología , Antiprotozoarios/química , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Eritrocitos/metabolismo , Línea Celular , Leishmania mexicana/efectos de los fármacos , Leishmania mexicana/metabolismo , Células THP-1 , Factor de Necrosis Tumoral alfa/metabolismo
9.
Nutrients ; 16(18)2024 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-39339767

RESUMEN

BACKGROUND: Capsaicin, a bioactive compound found in peppers, is recognized for its anti-inflammatory, antioxidant, and anti-lipidemic properties. This study aimed to evaluate the effects of capsaicin on atherosclerosis progression. METHODS: Apolipoprotein E knockout mice and their C57BL/6 controls were utilized to assess blood lipid profile, inflammatory status, and atherosclerotic lesions. We also examined the influence of capsaicin on cholesterol influx and efflux, and the role of TRPV1 and PPARγ signaling pathways in bone marrow-derived macrophages. RESULTS: Capsaicin treatment reduced weight gain, visceral adiposity, blood triglycerides, and total and non-HDL cholesterol. These improvements were associated with a reduction in atherosclerotic lesions in the aorta and carotid. Capsaicin also improved hepatic oxidative and inflammatory status. Systemic inflammation was also reduced, as indicated by reduced leukocyte rolling and adhesion on the mesenteric plexus. Capsaicin decreased foam cell formation by reducing cholesterol influx through scavenger receptor A and increasing cholesterol efflux via ATP-binding cassette transporter A1, an effect primarily linked to TRPV1 activation. CONCLUSIONS: These findings underscore the potential of capsaicin as a promising agent for atherosclerosis prevention, highlighting its comprehensive role in modulating lipid metabolism, foam cell formation, and inflammatory responses.


Asunto(s)
Aterosclerosis , Capsaicina , Células Espumosas , Inflamación , PPAR gamma , Canales Catiónicos TRPV , Animales , Masculino , Ratones , Antiinflamatorios/farmacología , Aterosclerosis/prevención & control , Aterosclerosis/tratamiento farmacológico , Transportador 1 de Casete de Unión a ATP/metabolismo , Capsaicina/farmacología , Colesterol/sangre , Colesterol/metabolismo , Células Espumosas/efectos de los fármacos , Células Espumosas/metabolismo , Inflamación/tratamiento farmacológico , Metabolismo de los Lípidos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Noqueados para ApoE , PPAR gamma/metabolismo , Transducción de Señal/efectos de los fármacos , Canales Catiónicos TRPV/metabolismo
10.
Biochem Biophys Res Commun ; 733: 150712, 2024 11 12.
Artículo en Inglés | MEDLINE | ID: mdl-39317112

RESUMEN

Cisplatin (CDDP) is an antineoplastic drug whose adverse effects include hepatotoxicity. The inflammatory process is crucial in the progression of liver injuries. Exercise is known for its anti-inflammatory effects, but the influence of different training modalities on hepatoprotection is still unclear. This study aims to compare the impacts between preconditioning with high-intensity interval training (HIIT) and traditional continuous training of low (LT) and moderate (MT) intensities on inflammatory markers in Wistar female rats with CDDP-induced hepatotoxicity. Thirty-five rats were divided into five groups: control and sedentary (C + Sed), treated with CDDP and sedentary (CDDP + Sed), treated with CDDP and subjected to LT (CDDP + LT), treated with CDDP and subjected to MT (CDDP + MT), and treated with CDDP and subjected to HIIT (CDDP + HIIT). The training protocols consisted of treadmill running for 8 weeks before CDDP treatment. The rats were euthanized 7 days after the treatment. Liver samples were collected to evaluate the expression of various inflammatory markers and types of macrophages. Our results indicated that HIIT was the only protocol to prevent the increase in all analyzed pro-inflammatory cytokines and reduce the number of ED-1-positive cells, attenuating the TLR4/NF-κB signaling pathway in the liver. Additionally, HIIT increased the anti-inflammatory cytokine IL-10 and regulated M1/M2 macrophage polarization. Thus, this study suggests that preconditioning with HIIT is more effective in promoting hepatoprotective effects than LT and MT, regulating inflammatory markers through modulation of the TLR4/NF-κB signaling pathway and M2 macrophage polarization in the hepatic tissue of female rats treated with CDDP.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Cisplatino , Entrenamiento de Intervalos de Alta Intensidad , Macrófagos , FN-kappa B , Condicionamiento Físico Animal , Transducción de Señal , Receptor Toll-Like 4 , Animales , Femenino , Ratas , Antineoplásicos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Cisplatino/efectos adversos , Cisplatino/toxicidad , Entrenamiento de Intervalos de Alta Intensidad/métodos , Inflamación/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , FN-kappa B/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo
11.
Food Funct ; 15(20): 10399-10413, 2024 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-39320081

RESUMEN

Macrophage activation plays a central role in the development of atherosclerotic plaques. Interaction with oxidized low-density lipoprotein (oxLDL) leads to macrophage differentiation into foam cells and oxylipin production, contributing to plaque formation. 7-Ketocholesterol (7KC) is an oxidative byproduct of cholesterol found in oxLDL particles and is considered a factor contributing to plaque progression. During atherosclerotic lesion regression or stabilization, macrophages undergo a transformation from a pro-inflammatory phenotype to a reparative anti-inflammatory state. Interleukin-10 (IL-10) and PGE1 appear to be crucial in resolving both acute and chronic inflammatory processes. After coffee consumption, the gut microbiota processes non-absorbed chlorogenic acids producing various lower size phenolic acids. These colonic catabolites, including dihydroferulic acid (DHFA), may exert various local and systemic effects. We focused on DHFA's impact on inflammation and oxidative stress in THP-1 macrophages exposed to oxLDL, 7KC, and lipopolysaccharides (LPS). Our findings reveal that DHFA inhibits the release of several pro-inflammatory mediators induced by LPS in macrophages, such as CCL-2, CCL-3, CCL-5, TNF-α, IL-6, and IL-17. Furthermore, DHFA reduces IL-18 and IL-1ß secretion in an inflammasome-like model. DHFA demonstrated additional benefits: it decreased oxLDL uptake and CD36 expression induced by oxLDL, regulated reactive oxygen species (ROS) and 8-isoprostane secretion (indicating oxidative stress modulation), and selectively increased IL-10 and PGE1 levels in the presence of inflammatory stimuli (LPS and 7KC). Finally, our study highlights the pivotal role of PGE1 in foam cell inhibition and inflammation regulation within activated macrophages. This study highlights DHFA's potential as an antioxidant and anti-inflammatory agent, particularly due to its ability to induce PGE1 and IL-10.


Asunto(s)
Ácidos Cumáricos , Cetocolesteroles , Lipopolisacáridos , Lipoproteínas LDL , Macrófagos , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Lipoproteínas LDL/metabolismo , Lipopolisacáridos/farmacología , Cetocolesteroles/farmacología , Ácidos Cumáricos/farmacología , Antiinflamatorios/farmacología , Polifenoles/farmacología , Activación de Macrófagos/efectos de los fármacos , Colon/metabolismo , Colon/efectos de los fármacos , Interleucina-10/metabolismo , Estrés Oxidativo/efectos de los fármacos , Mediadores de Inflamación/metabolismo
12.
PLoS Pathog ; 20(9): e1012179, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39331659

RESUMEN

Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne +ssRNA virus belonging to the Togaviridae. VEEV is found throughout Central and South America and is responsible for periodic epidemic/epizootic outbreaks of febrile and encephalitic disease in equines and humans. Endemic/enzootic VEEV is transmitted between Culex mosquitoes and sylvatic rodents, whereas epidemic/epizootic VEEV is transmitted between mosquitoes and equids, which serve as amplification hosts during outbreaks. Epizootic VEEV emergence has been shown to arise from mutation of enzootic VEEV strains. Specifically, epizootic VEEV has been shown to acquire amino acid mutations in the E2 viral glycoprotein that facilitate viral entry and equine amplification. However, the abundance of synonymous mutations which accumulate across the epizootic VEEV genome suggests that other viral determinants such as RNA secondary structure may also play a role in VEEV emergence. In this study we identify novel RNA structures in the E1 gene which specifically alter replication fitness of epizootic VEEV in macrophages but not other cell types. We show that SNPs are conserved within epizootic lineages and that RNA structures are conserved across different lineages. We also identified several novel RNA-binding proteins that are necessary for altered macrophage replication. These results suggest that emergence of VEEV in nature requires multiple mutations across the viral genome, some of which alter cell-type specific replication fitness in an RNA structure-dependent manner.


Asunto(s)
Virus de la Encefalitis Equina Venezolana , Encefalomielitis Equina Venezolana , Macrófagos , ARN Viral , Replicación Viral , Virus de la Encefalitis Equina Venezolana/genética , Virus de la Encefalitis Equina Venezolana/fisiología , Animales , Replicación Viral/fisiología , Encefalomielitis Equina Venezolana/virología , ARN Viral/genética , ARN Viral/metabolismo , Macrófagos/virología , Macrófagos/metabolismo , Caballos , Ratones , Conformación de Ácido Nucleico , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/metabolismo
13.
Biochemistry ; 63(16): 2023-2029, 2024 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-39106042

RESUMEN

The kallikrein-related peptidase KLK2 has restricted expression in the prostate luminal epithelium, and its protein target is unknown. The present work reports the hydrolytic activities of KLK2 on libraries of fluorescence resonance energy-transfer peptides from which the sequence SYRIF was the most susceptible substrate for KLK2. The sequence SYRIF is present at the extracellular N-terminal segment (58SYRIF63Q) of IL-10R2. KLK2 was fully active at pH 8.0-8.2, found only in prostate inflammatory conditions, and strongly activated by sodium citrate and glycosaminoglycans, the quantities and structures controlled by prostate cells. Bone-marrow-derived macrophages (BMDM) have IL-10R2 expressed on the cell surface, which is significantly reduced after KLK2 treatment, as determined by flow cytometry (FACS analysis). The IL-10 inhibition of the inflammatory response to LPS/IFN-γ in BMDM cells due to decreased nitric oxide, TNF-α, and IL-12 p40 levels is significantly reduced upon treatment of these cells with KLK2. Similar experiments with KLK3 did not show these effects. These observations indicate that KLK2 proteolytic activity plays a role in prostate inflammation and makes KLK2 a promising target for prostatitis treatment.


Asunto(s)
Calicreínas , Humanos , Masculino , Calicreínas/metabolismo , Calicreínas/química , Arginina/metabolismo , Arginina/química , Próstata/metabolismo , Próstata/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Animales , Ratones , Péptidos/química , Péptidos/farmacología , Péptidos/metabolismo , Dominios Proteicos , Interleucina-10/metabolismo , Especificidad por Sustrato
14.
Nat Microbiol ; 9(10): 2710-2726, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39191887

RESUMEN

Aspergillus fumigatus causes aspergillosis and relies on asexual spores (conidia) for initiating host infection. There is scarce information about A. fumigatus proteins involved in fungal evasion and host immunity modulation. Here we analysed the conidial surface proteome of A. fumigatus, two closely related non-pathogenic species, Aspergillus fischeri and Aspergillus oerlinghausenensis, as well as pathogenic Aspergillus lentulus, to identify such proteins. After identifying 62 proteins exclusively detected on the A. fumigatus conidial surface, we assessed null mutants for 42 genes encoding these proteins. Deletion of 33 of these genes altered susceptibility to macrophage, epithelial cells and cytokine production. Notably, a gene that encodes a putative glycosylasparaginase, modulating levels of the host proinflammatory cytokine IL-1ß, is important for infection in an immunocompetent murine model of fungal disease. These results suggest that A. fumigatus conidial surface proteins are important for evasion and modulation of the immune response at the onset of fungal infection.


Asunto(s)
Aspergilosis , Aspergillus fumigatus , Proteínas Fúngicas , Evasión Inmune , Proteoma , Esporas Fúngicas , Aspergillus fumigatus/inmunología , Aspergillus fumigatus/genética , Animales , Esporas Fúngicas/inmunología , Ratones , Proteoma/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/inmunología , Aspergilosis/inmunología , Aspergilosis/microbiología , Humanos , Interacciones Huésped-Patógeno/inmunología , Interacciones Huésped-Patógeno/genética , Macrófagos/inmunología , Macrófagos/microbiología , Macrófagos/metabolismo , Citocinas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/inmunología , Modelos Animales de Enfermedad , Células Epiteliales/microbiología , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Femenino
15.
Dis Model Mech ; 17(8)2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39114912

RESUMEN

The Bacillus Calmette-Guérin (BCG) vaccine is the oldest cancer immunotherapeutic agent in use. Despite its effectiveness, its initial mechanisms of action remain largely unknown. Here, we elucidate the earliest cellular mechanisms involved in BCG-induced tumor clearance. We developed a fast preclinical in vivo assay to visualize in real time and at single-cell resolution the initial interactions among bladder cancer cells, BCG and innate immunity using the zebrafish xenograft model. We show that BCG induced the recruitment and polarization of macrophages towards a pro-inflammatory phenotype, accompanied by induction of the inflammatory cytokines tnfa, il1b and il6 in the tumor microenvironment. Macrophages directly induced apoptosis of human cancer cells through zebrafish TNF signaling. Macrophages were crucial for this response as their depletion completely abrogated the BCG-induced phenotype. Contrary to the general concept that macrophage anti-tumoral activities mostly rely on stimulating an effective adaptive response, we demonstrate that macrophages alone can induce tumor apoptosis and clearance. Thus, our results revealed an additional step to the BCG-induced tumor immunity model, while providing proof-of-concept experiments demonstrating the potential of this unique model to test innate immunomodulators.


Asunto(s)
Apoptosis , Vacuna BCG , Macrófagos , Transducción de Señal , Neoplasias de la Vejiga Urinaria , Pez Cebra , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/inmunología , Animales , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Vacuna BCG/farmacología , Vacuna BCG/uso terapéutico , Transducción de Señal/efectos de los fármacos , Humanos , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Microambiente Tumoral
16.
Nature ; 633(8029): 417-425, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39198650

RESUMEN

Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette-Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis1. Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFNγ. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette-Guérin disease and tuberculosis3. Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents.


Asunto(s)
Macrófagos , Tuberculosis Pulmonar , Factores de Necrosis Tumoral , Adulto , Femenino , Humanos , Masculino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Homocigoto , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/inmunología , Células Madre Pluripotentes Inducidas/citología , Inflamación/inmunología , Interferón gamma/inmunología , Mutación con Pérdida de Función , Pulmón/citología , Pulmón/efectos de los fármacos , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Macrófagos Alveolares/citología , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/microbiología , Macrófagos Alveolares/patología , Mycobacterium tuberculosis/inmunología , Fenotipo , Especies Reactivas de Oxígeno/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/deficiencia , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Estallido Respiratorio , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/genética , Inhibidores del Factor de Necrosis Tumoral/farmacología , Factores de Necrosis Tumoral/deficiencia , Factores de Necrosis Tumoral/genética , Adolescente , Adulto Joven
17.
Biochem Pharmacol ; 229: 116480, 2024 11.
Artículo en Inglés | MEDLINE | ID: mdl-39128587

RESUMEN

Alamandine (ALA) exerts protective effects similar to angiotensin (Ang) (1-7) through Mas-related G protein-coupled receptor type D receptor (MrgDR) activation, distinct from Mas receptor (MasR). ALA induces anti-inflammatory effects in mice but its impact in human macrophages remains unclear. We aimed to investigate the anti-inflammatory effects of ALA in human macrophages. Interleukin (IL)-6 and IL-1ß were measured by ELISA in human THP-1 macrophages and human monocyte-derived macrophages exposed to lipopolysaccharide (LPS). Consequences of MasR-MrgDR heteromerization were investigated in transfected HEK293T cells. ALA decreased IL-6 and IL-1ß secretion in LPS-activated THP-1 macrophages. The ALA-induced decrease in IL-6 but not in IL-1ß was prevented by MasR blockade and MasR downregulation, suggesting MasR-MrgDR interaction. In human monocyte-derived M1 macrophages, ALA decreased IL-1ß secretion independently of MasR. MasR-MrgDR interaction was confirmed in THP-1 macrophages, human monocyte-derived macrophages, and transfected HEK293T cells. MasR and MrgDR formed a constitutive heteromer that was not influenced by ALA. ALA promoted Akt and ERK1/2 activation only in cells expressing MasR-MrgDR heteromers, and this effect was prevented by MasR blockade. While Ang-(1-7) reduced cellular proliferation in MasR -but not MrgDR- expressing cells, ALA antiproliferative effect was elicited in cells expressing MasR-MrgDR heteromers. ALA also induced an antiproliferative response in THP-1 cells and this effect was abolished by MasR blockade, reinforcing MasR-MrgDR interaction. MasR-MrgDR heteromerization is crucial for ALA-induced anti-inflammatory and antiproliferative responses in human macrophages. This study broaden our knowledge of the protective axis of the RAS, thus enabling novel therapeutic approaches in inflammatory-associated diseases.


Asunto(s)
Proliferación Celular , Interleucina-6 , Macrófagos , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas , Receptores Acoplados a Proteínas G , Sistema Renina-Angiotensina , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Proliferación Celular/efectos de los fármacos , Células HEK293 , Receptores Acoplados a Proteínas G/metabolismo , Interleucina-6/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Células THP-1 , Multimerización de Proteína/efectos de los fármacos , Oligopéptidos
18.
Biomed Mater ; 19(5)2024 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-39121890

RESUMEN

This study delves into the potential of amorphous titanium oxide (aTiO2) nano-coating to enhance various critical aspects of non-Ti-based metallic orthopedic implants. These implants, such as medical-grade stainless steel (SS), are widely used for orthopedic devices that demand high strength and durability. The aTiO2nano-coating, deposited via magnetron sputtering, is a unique attempt to improve the osteogenesis, the inflammatory response, and to reduce bacterial colonization on SS substrates. The study characterized the nanocoated surfaces (SS-a TiO2) in topography, roughness, wettability, and chemical composition. Comparative samples included uncoated SS and sandblasted/acid-etched Ti substrates (Ti). The biological effects were assessed using human mesenchymal stem cells (MSCs) and primary murine macrophages. Bacterial tests were carried out with two aerobic pathogens (S. aureusandS. epidermidis) and an anaerobic bacterial consortium representing an oral dental biofilm. Results from this study provide strong evidence of the positive effects of the aTiO2nano-coating on SS surfaces. The coating enhanced MSC osteoblastic differentiation and exhibited a response similar to that observed on Ti surfaces. Macrophages cultured on aTiO2nano-coating and Ti surfaces showed comparable anti-inflammatory phenotypes. Most significantly, a reduction in bacterial colonization across tested species was observed compared to uncoated SS substrates, further supporting the potential of aTiO2nano-coating in biomedical applications. The findings underscore the potential of magnetron-sputtering deposition of aTiO2nano-coating on non-Ti metallic surfaces such as medical-grade SS as a viable strategy to enhance osteoinductive factors and decrease pathogenic bacterial adhesion. This could significantly improve the performance of metallic-based biomedical devices beyond titanium.


Asunto(s)
Materiales Biocompatibles Revestidos , Macrófagos , Ensayo de Materiales , Células Madre Mesenquimatosas , Osteogénesis , Acero Inoxidable , Propiedades de Superficie , Titanio , Titanio/química , Acero Inoxidable/química , Animales , Humanos , Células Madre Mesenquimatosas/citología , Ratones , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Macrófagos/metabolismo , Osteogénesis/efectos de los fármacos , Diferenciación Celular , Prótesis e Implantes , Osteoblastos/citología , Staphylococcus aureus/efectos de los fármacos , Biopelículas , Staphylococcus epidermidis/efectos de los fármacos , Adhesión Bacteriana , Humectabilidad
19.
Int J Mol Sci ; 25(15)2024 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-39126003

RESUMEN

Periapical lesions are common pathologies affecting the alveolar bone, often initiated by intraradicular lesions resulting from microbial exposure to dental pulp. These microorganisms trigger inflammatory and immune responses. When endodontic treatment fails to eliminate the infection, periapical lesions persist, leading to bone loss. The RANK/RANKL/OPG pathway plays a crucial role in both the formation and the destruction of the bone. In this study, the objective was to inhibit the RANK/RANKL pathway in vitro within exposed Thp-1 macrophages to endodontic microorganisms, specifically Enterococcus faecalis, which was isolated from root canals of 20 patients with endodontic secondary/persistent infection, symptomatic and asymptomatic, and utilizing an α-IRAK-4 inhibitor, we introduced endodontic microorganisms and/or lipoteichoic acid from Streptococcus spp. to cellular cultures in a culture plate, containing thp-1 cells and/or PBMC from patients with apical periodontitis. Subsequently, we assessed the percentages of RANK+, RANKL+, and OPG+ cells through flow cytometry and measured the levels of several inflammatory cytokines (IL-1ß, TNF-α, IL-6, IL-8, IL-10, and IL-12p70) in the cellular culture supernatant through a CBA kit and performed analysis by flow cytometry. A significant difference was observed in the percentages of RANK+RANKL+, OPG+ RANKL+ cells in thp-1 cells and PBMCs from patients with apical periodontitis. The findings revealed significant differences in the percentages of the evaluated cells, highlighting the novel role of the IRAK-4 inhibitor in addressing this oral pathology, apical periodontitis, where bone destruction is observed.


Asunto(s)
Macrófagos , Periodontitis Periapical , Ligando RANK , Receptor Activador del Factor Nuclear kappa-B , Transducción de Señal , Humanos , Ligando RANK/metabolismo , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Células THP-1 , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Periodontitis Periapical/metabolismo , Periodontitis Periapical/microbiología , Periodontitis Periapical/patología , Citocinas/metabolismo , Enterococcus faecalis , Lipopolisacáridos , Cavidad Pulpar/microbiología , Cavidad Pulpar/metabolismo , Masculino , Osteoprotegerina/metabolismo , Adulto , Ácidos Teicoicos/farmacología
20.
Curr Genet ; 70(1): 14, 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-39150461

RESUMEN

In mammals, enteric salmonellas can use tetrathionate (ttr), formed as a by-product from the inflammatory process in the intestine, as electron acceptor in anaerobic respiration, and it can fuel its energy metabolism by degrading the microbial fermentation product 1,2-propanediol. However, recent studies have shown that this mechanism is not important for Salmonella infection in the intestine of poultry, while it prolongs the persistence of Salmonella at systemic sites in this species. In the current study, we show that ΔttrApduA strains of Salmonella enterica have lower net survival within chicken-derived HD-11 macrophages, as CFU was only 2.3% (S. Enteritidis ΔttrApduA), 2.3% (S. Heidelberg ΔttrApduA), and 3.0% (S. Typhimurium ΔttrApduA) compared to wild-type strains after 24 h inside HD-11 macrophage cells. The difference was not related to increased lysis of macrophages, and deletion of ttrA and pduA did not impair the ability of the strains to grow anaerobically. Further studies are indicated to determine the reason why Salmonella ΔttrApduA strains survive less well inside macrophage cell lines.


Asunto(s)
Pollos , Macrófagos , Salmonella enterica , Macrófagos/microbiología , Macrófagos/inmunología , Macrófagos/metabolismo , Animales , Pollos/microbiología , Salmonella enterica/genética , Línea Celular , Eliminación de Gen , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Salmonelosis Animal/microbiología , Salmonelosis Animal/inmunología , Viabilidad Microbiana/genética
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