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Cardiomyocytes are subjected to the intense mechanical stress and metabolic demands of the beating heart. It is unclear whether these cells, which are long-lived and rarely renew, manage to preserve homeostasis on their own. While analyzing macrophages lodged within the healthy myocardium, we discovered that they actively took up material, including mitochondria, derived from cardiomyocytes. Cardiomyocytes ejected dysfunctional mitochondria and other cargo in dedicated membranous particles reminiscent of neural exophers, through a process driven by the cardiomyocyte's autophagy machinery that was enhanced during cardiac stress. Depletion of cardiac macrophages or deficiency in the phagocytic receptor Mertk resulted in defective elimination of mitochondria from the myocardial tissue, activation of the inflammasome, impaired autophagy, accumulation of anomalous mitochondria in cardiomyocytes, metabolic alterations, and ventricular dysfunction. Thus, we identify an immune-parenchymal pair in the murine heart that enables transfer of unfit material to preserve metabolic stability and organ function. VIDEO ABSTRACT.
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Macrófagos/metabolismo , Mitocondrias/metabolismo , Miocitos Cardíacos/metabolismo , Anciano , Animales , Apoptosis , Autofagia , Femenino , Corazón/fisiología , Homeostasis , Humanos , Macrófagos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Mitocondrias/fisiología , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/fisiología , Fagocitosis/fisiología , Especies Reactivas de Oxígeno/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Tirosina Quinasa c-Mer/metabolismoRESUMEN
Resolution of inflammation is essential for tissue homeostasis and represents a promising approach to inflammatory disorders. Here we found that developmental endothelial locus-1 (DEL-1), a secreted protein that inhibits leukocyte-endothelial adhesion and inflammation initiation, also functions as a non-redundant downstream effector in inflammation clearance. In human and mouse periodontitis, waning of inflammation was correlated with DEL-1 upregulation, whereas resolution of experimental periodontitis failed in DEL-1 deficiency. This concept was mechanistically substantiated in acute monosodium-urate-crystal-induced inflammation, where the pro-resolution function of DEL-1 was attributed to effective apoptotic neutrophil clearance (efferocytosis). DEL-1-mediated efferocytosis induced liver X receptor-dependent macrophage reprogramming to a pro-resolving phenotype and was required for optimal production of at least certain specific pro-resolving mediators. Experiments in transgenic mice with cell-specific overexpression of DEL-1 linked its anti-leukocyte-recruitment action to endothelial cell-derived DEL-1 and its efferocytic/pro-resolving action to macrophage-derived DEL-1. Thus, the compartmentalized expression of DEL-1 facilitates distinct homeostatic functions in an appropriate context that can be harnessed therapeutically.
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Proteínas Portadoras/metabolismo , Inflamación/inmunología , Macrófagos/fisiología , Neutrófilos/inmunología , Periodontitis/inmunología , Adulto , Animales , Proteínas de Unión al Calcio , Proteínas Portadoras/genética , Moléculas de Adhesión Celular , Reprogramación Celular , Citocinas/metabolismo , Regulación de la Expresión Génica , Humanos , Inflamación/inducido químicamente , Péptidos y Proteínas de Señalización Intercelular , Células K562 , Receptores X del Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FagocitosisRESUMEN
Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate-SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation.
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Inflamación/inmunología , Macrófagos/inmunología , Obesidad/inmunología , Receptores Acoplados a Proteínas G/inmunología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/inmunología , Tejido Adiposo/metabolismo , Animales , Células Cultivadas , Citocinas/genética , Citocinas/inmunología , Citocinas/metabolismo , Perfilación de la Expresión Génica/métodos , Humanos , Inflamación/genética , Inflamación/metabolismo , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Obesidad/genética , Obesidad/metabolismo , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/genética , Ácido Succínico/inmunología , Ácido Succínico/metabolismo , Ácido Succínico/farmacología , Células THP-1RESUMEN
Unique among leukocytes, neutrophils follow daily cycles of release from and migration back into the bone marrow, where they are eliminated. Because removal of dying cells generates homeostatic signals, we explored whether neutrophil elimination triggers circadian events in the steady state. Here, we report that the homeostatic clearance of neutrophils provides cues that modulate the physiology of the bone marrow. We identify a population of CD62L(LO) CXCR4(HI) neutrophils that have "aged" in the circulation and are eliminated at the end of the resting period in mice. Aged neutrophils infiltrate the bone marrow and promote reductions in the size and function of the hematopoietic niche. Modulation of the niche depends on macrophages and activation of cholesterol-sensing nuclear receptors and is essential for the rhythmic egress of hematopoietic progenitors into the circulation. Our results unveil a process that synchronizes immune and hematopoietic rhythms and expand the ascribed functions of neutrophils beyond inflammation. PAPERFLICK:
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Médula Ósea/fisiología , Ritmo Circadiano , Neutrófilos/citología , Neutrófilos/fisiología , Animales , Movimiento Celular , Senescencia Celular , Femenino , Células Madre Hematopoyéticas/metabolismo , Homeostasis , Receptores X del Hígado , Masculino , Ratones , Ratones Endogámicos C57BL , Neutrófilos/inmunología , Receptores Nucleares Huérfanos/metabolismoRESUMEN
The role of liver X receptors (LXR) in rheumatoid arthritis (RA) remains controversial. We studied the effect of LXR agonists on fibroblast-like synoviocytes (FLS) from RA patients and the K/BxN arthritis model in LXRα and ß double-deficient (Nr1h2/3-/-) mice. Two synthetic LXR agonists, GW3965 and T0901317, were used to activate LXRs and investigate their effects on cell growth, proliferation and matrix metalloproteinases, and chemokine production in cultured FLS from RA patients. The murine model K/BxN serum transfer of inflammatory arthritis in Nr1h2/3-/- animals was used to investigate the role of LXRs on joint inflammation in vivo. LXR agonists inhibited the FLS proliferative capacity in response to TNF, the chemokine-induced migration, the collagenase activity in FLS supernatant and FLS CXCL12 production. In the K/BxN mouse model, Nr1h2/3-/- animals showed aggravated arthritis, histological inflammation, and joint destruction, as well as an increase in synovial metalloproteases and expression of proinflammatory mediators such as IL-1ß and CCL2 in joints compared with wild type animals. Taken together, these data underscore the importance of LXRs in modulating the joint inflammatory response and highlight them as potential therapeutic targets in RA.
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Macrophages are professional phagocytic cells that orchestrate innate immune responses and have considerable phenotypic diversity at different anatomical locations. However, the mechanisms that control the heterogeneity of tissue macrophages are not well characterized. Here we found that the nuclear receptor LXRα was essential for the differentiation of macrophages in the marginal zone (MZ) of the spleen. LXR-deficient mice were defective in the generation of MZ and metallophilic macrophages, which resulted in abnormal responses to blood-borne antigens. Myeloid-specific expression of LXRα or adoptive transfer of wild-type monocytes restored the MZ microenvironment in LXRα-deficient mice. Our results demonstrate that signaling via LXRα in myeloid cells is crucial for the generation of splenic MZ macrophages and identify an unprecedented role for a nuclear receptor in the generation of specialized macrophage subsets.
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Hematopoyesis/inmunología , Macrófagos/inmunología , Receptores Nucleares Huérfanos/inmunología , Bazo/inmunología , Animales , Benzoatos/farmacología , Bencilaminas/farmacología , Diferenciación Celular/inmunología , Citometría de Flujo , Inmunidad Celular/inmunología , Inmunohistoquímica , Receptores X del Hígado , Macrófagos/citología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microscopía Fluorescente , Receptores Nucleares Huérfanos/agonistas , Transducción de Señal/inmunología , Organismos Libres de Patógenos Específicos , Bazo/citologíaRESUMEN
Liver X receptors (LXRs) are regulators of cholesterol metabolism that also modulate immune responses. Inactivation of LXR α and ß in mice leads to autoimmunity; however, how the regulation of cholesterol metabolism contributes to autoimmunity is unclear. Here we found that cholesterol loading of CD11c+ cells triggered the development of autoimmunity, whereas preventing excess lipid accumulation by promoting cholesterol efflux was therapeutic. LXRß-deficient mice crossed to the hyperlipidemic ApoE-deficient background or challenged with a high-cholesterol diet developed autoantibodies. Cholesterol accumulation in lymphoid organs promoted T cell priming and stimulated the production of the B cell growth factors Baff and April. Conversely, B cell expansion and the development of autoantibodies in ApoE/LXR-ß-deficient mice was reversed by ApoA-I expression. These findings implicate cholesterol imbalance as a contributor to immune dysfunction and suggest that stimulating HDL-dependent reverse cholesterol transport could be beneficial in the setting of autoimmune disease.
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Células Presentadoras de Antígenos/inmunología , Enfermedades Autoinmunes/inmunología , Colesterol/metabolismo , Hipercolesterolemia/metabolismo , Animales , Enfermedades Autoinmunes/metabolismo , Antígeno CD11c/inmunología , Colesterol/inmunología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Perfilación de la Expresión Génica , Hipercolesterolemia/inmunología , Receptores X del Hígado/inmunología , Receptores X del Hígado/metabolismo , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , TranscriptomaRESUMEN
Lung type 2 pneumocytes (T2Ps) and alveolar macrophages (AMs) play crucial roles in the synthesis, recycling and catabolism of surfactant material, a lipid/protein fluid essential for respiratory function. The liver X receptors (LXR), LXRα and LXRß, are transcription factors important for lipid metabolism and inflammation. While LXR activation exerts anti-inflammatory actions in lung injury caused by lipopolysaccharide (LPS) and other inflammatory stimuli, the full extent of the endogenous LXR transcriptional activity in pulmonary homeostasis is incompletely understood. Here, using mice lacking LXRα and LXRß as experimental models, we describe how the loss of LXRs causes pulmonary lipidosis, pulmonary congestion, fibrosis and chronic inflammation due to defective de novo synthesis and recycling of surfactant material by T2Ps and defective phagocytosis and degradation of excess surfactant by AMs. LXR-deficient T2Ps display aberrant lamellar bodies and decreased expression of genes encoding for surfactant proteins and enzymes involved in cholesterol, fatty acids, and phospholipid metabolism. Moreover, LXR-deficient lungs accumulate foamy AMs with aberrant expression of cholesterol and phospholipid metabolism genes. Using a house dust mite aeroallergen-induced mouse model of asthma, we show that LXR-deficient mice exhibit a more pronounced airway reactivity to a methacholine challenge and greater pulmonary infiltration, indicating an altered physiology of LXR-deficient lungs. Moreover, pretreatment with LXR agonists ameliorated the airway reactivity in WT mice sensitized to house dust mite extracts, confirming that LXR plays an important role in lung physiology and suggesting that agonist pharmacology could be used to treat inflammatory lung diseases.
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Homeostasis , Receptores X del Hígado , Macrófagos Alveolares , Neumonía , Surfactantes Pulmonares , Transducción de Señal , Animales , Receptores X del Hígado/metabolismo , Receptores X del Hígado/genética , Surfactantes Pulmonares/metabolismo , Ratones , Neumonía/metabolismo , Neumonía/patología , Macrófagos Alveolares/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Pulmón/metabolismo , Pulmón/patología , Células Epiteliales Alveolares/metabolismo , Asma/metabolismo , Asma/patología , Asma/genética , Colesterol/metabolismo , Metabolismo de los Lípidos , FagocitosisRESUMEN
We report on precision spectroscopy of the 6s^{2} ^{1}S_{0}â6s6p ^{3}P_{1} intercombination line of mercury in the deep ultraviolet, by means of a frequency-comb referenced, wavelength-modulated, saturated absorption technique. This method allowed us to perform sub-Doppler investigations with an absolute frequency axis at 254 nm, while ensuring a relatively high signal-to-noise ratio. The absolute line center frequencies of the ^{200}Hg and ^{202}Hg bosonic isotopes were measured with a global uncertainty of 8 and 15 kHz (namely, 6.8×10^{-12} and 1.3×10^{-11}, in relative terms), respectively, the statistical and systematic components being significantly reduced as compared to past determinations. This remarkable result was achieved also thanks to an in-depth study of the ac Stark effect. Furthermore, we found the most accurate ^{200}Hg-^{202}Hg isotope shift ever obtained before, namely, 5 295 57 0±15_{stat}±8_{syst} kHz.
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Monocyte-derived macrophages contribute to pathogenesis in inflammatory diseases and their effector functions greatly depend on the prevailing extracellular milieu. Whereas M-CSF primes macrophages for acquisition of an anti-inflammatory profile, GM-CSF drives the generation of T cell-stimulatory and pro-inflammatory macrophages. Liver X Receptors (LXRα and LXRß) are nuclear receptors that control cholesterol metabolism and regulate differentiation of tissue-resident macrophages. Macrophages from rheumatoid arthritis and other inflammatory pathologies exhibit an enriched LXR pathway, and recent reports have shown that LXR activation raises pro-inflammatory effects and impairs the acquisition of the anti-Inflammatory profile of M-CSF-dependent monocyte-derived macrophages (M-MØ). We now report that LXR inhibition prompts the acquisition of an anti-inflammatory gene and functional profile of macrophages generated within a pathological environment (synovial fluid from Rheumatoid Arthritis patients) as well as during the GM-CSF-dependent differentiation of human monocyte-derived macrophages (GM-MØ). Mechanistically, inhibition of LXR results in macrophages with higher expression of the v-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homolog B (MAFB) transcription factor, which governs the macrophage anti-inflammatory profile, as well as over-expression of MAFB-regulated genes. Indeed, gene silencing experiments on human macrophages evidenced that MAFB is required for the LXR inhibitor to enhance the anti-inflammatory nature of human macrophages. As a whole, our results demonstrate that LXR inhibition prompts the acquisition of an anti-inflammatory transcriptional and functional profile of human macrophages in a MAFB-dependent manner, and propose the use of LXR antagonists as potential therapeutic alternatives in macrophage re-programming strategies during inflammatory responses.
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Artritis Reumatoide , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Humanos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Factor Estimulante de Colonias de Macrófagos/genética , Regulación hacia Arriba , Macrófagos/metabolismo , Artritis Reumatoide/patología , Antiinflamatorios/metabolismo , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismo , Factor de Transcripción MafB/genética , Factor de Transcripción MafB/metabolismoRESUMEN
Lamb dips of twenty lines in the P, Q, and R branches of the ν1 + ν3 + ν41 vibrational band of 12C2H2, in the spectral window of 7125-7230 cm-1, have been measured using an upgraded comb-calibrated frequency-stabilized cavity ring-down spectrometer, designed for extensive sub-Doppler measurements. Due to the large number of carefully executed Lamb-dip experiments, and to the extrapolation of absolute frequencies to zero pressure in each case, the combined average uncertainty of the measured line-center positions is 15 kHz (5 × 10-7 cm-1) with a 2-σ confidence level. Selection of the twenty lines was based on the theory of spectroscopic networks (SN), ensuring that a large number of transitions, measured previously by precision-spectroscopy investigations, could be connected to the para and ortho principal components of the SN of 12C2H2. The assembled SN contains 331 highly precise transitions, 119 and 121 of which are in the ortho and para principal components, respectively, while the rest remain in floating components. The para- and ortho-12C2H2 energy-level lists, determined during the present study, contain 82 and 80 entries, respectively, with an accuracy similar to that of the lines. Based on the newly assembled lists of para- and ortho-12C2H2 empirical energy levels, a line list, called TenkHz, has been generated. The TenkHz line list contains 282 entries in the spectral range of 5898.97-7258.87 cm-1; thus far, only 149 of them have been measured directly via precision spectroscopy. The TenkHz line list includes 35 intense lines that are missing in the HITRAN2020 database.
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In the course of atherogenesis, the spleen plays an important role in the regulation of extramedullary hematopoiesis, and in the control of circulating immune cells, which contributes to plaque progression. Here, we have investigated the role of splenic nucleotide-binding oligomerization domain 1 (NOD1) in the recruitment of circulating immune cells, as well as the involvement of this immune organ in extramedullary hematopoiesis in mice fed on a high-fat high-cholesterol diet (HFD). Under HFD conditions, the absence of NOD1 enhances the mobilization of immune cells, mainly neutrophils, from the bone marrow to the blood. To determine the effect of NOD1-dependent mobilization of immune cells under pro-atherogenic conditions, Apoe-/- and Apoe-/-Nod1-/- mice fed on HFD for 4 weeks were used. Splenic NOD1 from Apoe-/- mice was activated after feeding HFD as inferred by the phosphorylation of the NOD1 downstream targets RIPK2 and TAK1. Moreover, this activation was accompanied by the release of neutrophil extracellular traps (NETs), as determined by the increase in the expression of peptidyl arginine deiminase 4, and the identification of citrullinated histone H3 in this organ. This formation of NETs was significantly reduced in Apoe-/-Nod1-/- mice. Indeed, the presence of Ly6G+ cells and the lipidic content in the spleen of mice deficient in Apoe and Nod1 was reduced when compared to the Apoe-/- counterparts, which suggests that the mobilization and activation of circulating immune cells are altered in the absence of NOD1. Furthermore, confirming previous studies, Apoe-/-Nod1-/- mice showed a reduced atherogenic disease, and diminished recruitment of neutrophils in the spleen, compared to Apoe-/- mice. However, splenic artery ligation reduced the atherogenic burden in Apoe-/- mice an effect that, unexpectedly was lost in Apoe-/-Nod1-/- mice. Together, these results suggest that neutrophil accumulation and activity in the spleen are driven in part by NOD1 activation in mice fed on HFD, contributing in this way to regulating atherogenic progression.
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Aterosclerosis , Trampas Extracelulares , Animales , Apolipoproteínas E/metabolismo , Aterosclerosis/metabolismo , Dieta Alta en Grasa/efectos adversos , Trampas Extracelulares/metabolismo , Ratones , Ratones Noqueados , Infiltración Neutrófila , Bazo/metabolismoRESUMEN
Nuclear receptors (NRs) are a superfamily of ligand-activated transcription factors that act as biological sensors and use a combination of mechanisms to modulate positively and negatively gene expression in a spatial and temporal manner. The highly orchestrated biological actions of several NRs influence the proliferation, differentiation, and apoptosis of many different cell types. Synthetic ligands for several NRs have been the focus of extensive drug discovery efforts for cancer intervention. This review summarizes the roles in tumour growth and metastasis of several relevant NR family members, namely androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR), thyroid hormone receptor (TR), retinoic acid receptors (RARs), retinoid X receptors (RXRs), peroxisome proliferator-activated receptors (PPARs), and liver X receptors (LXRs). These studies are key to develop improved therapeutic agents based on novel modes of action with reduced side effects and overcoming resistance.
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Hormonas , Lípidos , Neoplasias , Receptores Citoplasmáticos y Nucleares , Animales , HumanosRESUMEN
Iron participates in myriad processes necessary to sustain life. During the past decades, great efforts have been made to understand iron regulation and function in health and disease. Indeed, iron is associated with both physiological (e.g., immune cell biology and function and hematopoiesis) and pathological (e.g., inflammatory and infectious diseases, ferroptosis and ferritinophagy) processes, yet few studies have addressed the potential functional link between iron, the aforementioned processes and extramedullary hematopoiesis, despite the obvious benefits that this could bring to clinical practice. Further investigation in this direction will shape the future development of individualized treatments for iron-linked diseases and chronic inflammatory disorders, including extramedullary hematopoiesis, metabolic syndrome, cardiovascular diseases and cancer.
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Ferroptosis , Hematopoyesis Extramedular , Trastornos del Metabolismo del Hierro , Homeostasis , Humanos , Hierro/metabolismoRESUMEN
We realized a UV laser spectrometer at 253.7 nm for Doppler broadening thermometry on the 1S0-3P1 intercombination line in mercury vapors. Our setup is based on the two-stage duplication of a 1014.8 nm diode laser in a fiber-coupled periodically poled lithium niobate waveguide crystal and a beta-barium borate crystal in enhancement cavity, and we exploit injection locking of a 507.4 nm diode laser to boost the available optical power after the first duplication. Our setup addresses spectroscopic features that allow the thermodynamic temperature determination of the atomic sample from the absorption profile with 10-6 accuracy. The realized UV laser source has 1×10-4 relative intensity stability, Gaussian shape, and over 10 GHz mode-hop-free tunable range. These features are crucial for the practical realization of the kelvin in the new International System of Units through a spectroscopic technique.
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Modulation transfer spectroscopy is used to demonstrate absolute frequency stabilization of an 8.6-µm-wavelength quantum cascade laser against a sub-Doppler absorption of the CHF3 molecule. The obtained spectral emission properties are thoroughly characterized through a self-referenced optical frequency comb, stabilized against either a GPS-disciplined Rb clock or a 1.54-µm Er-fiber laser locked to a high-finesse ultra-low-expansion optical cavity. Fractional long-term stability and accuracy at a level of 4×10-12 (at 100 s) and 3×10-10, respectively, are demonstrated, along with an emission linewidth as narrow as 10 kHz for observation times of 0.1 s.
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Macrophage phenotypic and functional heterogeneity derives from tissue-specific transcriptional signatures shaped by the local microenvironment. Most studies addressing the molecular basis for macrophage heterogeneity have focused on murine cells, whereas the factors controlling the functional specialization of human macrophages are less known. M-CSF drives the generation of human monocyte-derived macrophages with a potent anti-inflammatory activity upon stimulation. We now report that knockdown of MAFB impairs the acquisition of the anti-inflammatory profile of human macrophages, identify the MAFB-dependent gene signature in human macrophages and illustrate the coexpression of MAFB and MAFB-target genes in CD163+ tissue-resident and tumor-associated macrophages. The contribution of MAFB to the homeostatic/anti-inflammatory macrophage profile is further supported by the skewed polarization of monocyte-derived macrophages from multicentric carpotarsal osteolysis (Online Mendelian Inheritance in Man #166300), a pathology caused by mutations in the MAFB gene. Our results demonstrate that MAFB critically determines the acquisition of the anti-inflammatory transcriptional and functional profiles of human macrophages.
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Diferenciación Celular , Síndrome de Hajdu-Cheney/inmunología , Macrófagos/fisiología , Factor de Transcripción MafB/metabolismo , Monocitos/fisiología , Animales , Antiinflamatorios , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Diferenciación Celular/genética , Células Cultivadas , Microambiente Celular , Citocinas/metabolismo , Técnicas de Silenciamiento del Gen , Ontología de Genes , Síndrome de Hajdu-Cheney/genética , Homeostasis , Humanos , Factor Estimulante de Colonias de Macrófagos/metabolismo , Factor de Transcripción MafB/genética , Ratones , Mutación/genética , Receptores de Superficie Celular/metabolismo , Células Th2/inmunología , TranscriptomaRESUMEN
Photodynamic therapy (PDT) is a rising and hopeful treatment for solid tumors and others malignancies. PDT uses harmless visible light to activate a tumor-associated photosensitizer (PS). The excited PS generates cytotoxic reactive oxygen species (ROS) that induce damage and death of tumor cells. It is known that certain phytoalexins and phytoanticipins derived from plants often display a PS-like activity due to a phenalenone (PN) moiety-an efficient singlet oxygen photosensitizer-in its skeleton. The aim of this study is to explore the phototoxic properties of PN on the human cell line tumor-derived HL60 (acute promyelocytic leukemia) and to identify the cell-specific targets of ROS involved in the tumor cell death. Our results reveal that PN acts as an excellent PS, showing a potent antitumor cell activity in presence of light. PN-PDT generates intracellular ROS, via oxidation reaction mechanisms type I and II, resulting in an induction of apoptosis. Moreover, both extrinsic (through direct activation of caspase-3) and intrinsic (through mitochondrial depolarization) pathways of apoptosis are induced by PN-PDT. Using pharmacologic inhibitors, we also find that PN-PDT activates caspase-8/tBid and p38-MAPK, triggering the activation of the apoptotic pathways. Although, survival pathways are also promoted through PI3 K/Akt and JNK activation, the net result of PN-PDT is the tumor cell death. The present work identifies to PN, for the first time, as a potent photosensitizer in human tumor cell lines and proposes a mechanism by which ROS induces apoptosis of tumor cell.
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Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Caspasa 8/metabolismo , Fenalenos/farmacología , Fotoquimioterapia , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Fragmentación del ADN , Relación Dosis-Respuesta a Droga , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estructura Molecular , Neoplasias/genética , Neoplasias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de SeñalRESUMEN
Macrophage heterogeneity in the spleen has been long documented, with four subsets populating the different splenic compartments. The diverse environments on the splenic compartments determine their varied phenotype and functions. In the white pulp, highly phagocytic macrophages contribute to the generation of the immune response. The marginal zone contains two populations of macrophages, which also contribute to the immune response. Their strategic position in the bloodstream and their unique phenotype confer them a crucial role in the defense against blood borne pathogens, placing them at the crossroad between innate and adaptive immune responses. Macrophages in the red pulp are classically linked to homeostatic and metabolic functions in erythrocyte phagocytosis and iron recycling. We review here recent advances demonstrating the importance of macrophage ontogeny and organ development in determining the phenotype, transcriptional profile and, ultimately, the functions of the populations of splenic macrophages.
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Metabolismo Energético/inmunología , Homeostasis/inmunología , Macrófagos/inmunología , Fagocitosis/inmunología , Bazo/inmunología , Inmunidad Adaptativa/inmunología , Animales , Eritrocitos/inmunología , Humanos , Inmunidad Innata/inmunología , Bazo/citología , Bazo/metabolismoRESUMEN
Effective clearance of apoptotic cells by macrophages is essential for immune homeostasis. The transcriptional pathways that allow macrophages to sense and respond to apoptotic cells are poorly defined. We found that liver X receptor (LXR) signaling was important for both apoptotic cell clearance and the maintenance of immune tolerance. Apoptotic cell engulfment activated LXR and thereby induced the expression of Mer, a receptor tyrosine kinase critical for phagocytosis. LXR-deficient macrophages exhibited a selective defect in phagocytosis of apoptotic cells and an aberrant proinflammatory response to them. As a consequence of these defects, mice lacking LXRs manifested a breakdown in self-tolerance and developed autoantibodies and autoimmune glomerulonephritis. Treatment with an LXR agonist ameliorated disease progression in a mouse model of lupus-like autoimmunity. Thus, activation of LXR by apoptotic cells engages a virtuous cycle that promotes their own clearance and couples engulfment to the suppression of inflammatory pathways.