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BACKGROUND: Pulmonary fibrosis (PF) represents the pathologic end stage of several interstitial lung diseases (ILDs) associated with high morbidity and mortality rates. However, current treatments can only delay disease progression rather than provide a cure. The role of inflammation in PF progression is well-established, but new insights into immune regulation are fundamental for developing more efficient therapies. c-MET signaling has been implicated in the migratory capacity and effector functions of immune cells. Nevertheless, the role of this signaling pathway in the context of PF-associated lung diseases remains unexplored. METHODS: To determine the influence of c-MET in immune cells in the progression of pulmonary fibrosis, we used a conditional deletion of c-Met in immune cells. To induce pulmonary fibrosis mice were administered with bleomycin (BLM) intratracheally. Over the course of 21 days, mice were assessed for weight change, and after euthanasia at different timepoints, bronchoalveolar lavage fluid cells and lung tissue were assessed for inflammation and fibrosis. Furthermore, c-MET expression was assessed in cryobiopsy sections, bronchoalveolar lavage fluid cells samples and single cell RNA-sequencing dataset from human patients with distinct interstitial lung diseases. RESULTS: c-MET expression was induced in lung immune cells, specifically in T cells, interstitial macrophages, and neutrophils, during the inflammatory phase of BLM-induced PF mouse model. Deletion of c-Met in immune cells correlated with earlier weight recovery and improved survival of BLM-treated mice. Moreover, the deletion of c-Met in immune cells was associated with early recruitment of the immune cell populations, normally found to express c-MET, leading to a subsequent attenuation of the cytotoxic and proinflammatory environment. Consequently, the less extensive inflammatory response, possibly coupled with tissue repair, culminated in less exacerbated fibrotic lesions. Furthermore, c-MET expression was up-regulated in lung T cells from patients with fibrosing ILD, suggesting a potential involvement of c-MET in the development of fibrosing disease. CONCLUSIONS: These results highlight the critical contribution of c-MET signaling in immune cells to their enhanced uncontrolled recruitment and activation toward a proinflammatory and profibrotic phenotype, leading to the exacerbation of lung injury and consequent development of fibrosis.
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Ratones Endogámicos C57BL , Neumonía , Proteínas Proto-Oncogénicas c-met , Fibrosis Pulmonar , Animales , Femenino , Humanos , Masculino , Ratones , Bleomicina/toxicidad , Modelos Animales de Enfermedad , Pulmón/patología , Pulmón/metabolismo , Pulmón/inmunología , Ratones Noqueados , Neumonía/inducido químicamente , Neumonía/patología , Neumonía/metabolismo , Neumonía/inmunología , Neumonía/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Proteínas Proto-Oncogénicas c-met/genética , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/inmunología , Fibrosis Pulmonar/genéticaRESUMEN
To explore severity and progression biomarkers, we examined the clinical relevance of multiple cytokines and mediators involved in the inflammatory response in periodontitis. A cohort of 68 patients was enrolled in the study and periodontal status assessed by the current classification of periodontal diseases. Immune mediators present in saliva, of both patients and healthy controls, were quantified using a Legendplex-13 panel. Clinic parameters were significantly higher in PD patients compared with HC, with a strong significant association with the disease severity (stage) (p < 0.001), but not with progression (grade). The panel of immune mediators evidenced elevated levels of pro-inflammatory cytokines IL-6 and IL-1ß as disease established (p < 0.01). IL-1ß/IL-1RA ratio was increased in PD patients, being associated with disease stage. An anti-inflammatory response was spotted by higher IL-10. Lower levels of IL-23 and IP-10 were associated with disease severity. No significant statistical differences were found by grade classification. Moreover, salivary IL-1ß and IL-6 exhibited significant positive correlations with several clinical measurements (PI, BOP, PPD, CAL), while IP-10 showed a statistical negative correlation with BOP, PPD, and CAL. These insights highlight the complexity of the periodontitis inflammatory network and the potential of cytokines as biomarkers for refined diagnostic and therapeutic strategies.
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Biomarcadores , Interleucina-10 , Interleucina-1beta , Interleucina-6 , Periodontitis , Saliva , Índice de Severidad de la Enfermedad , Humanos , Biomarcadores/metabolismo , Femenino , Masculino , Saliva/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/análisis , Interleucina-6/metabolismo , Persona de Mediana Edad , Interleucina-10/metabolismo , Periodontitis/metabolismo , Periodontitis/patología , Periodontitis/inmunología , Adulto , Estudios de Casos y ControlesRESUMEN
Oxidation of PUFAs in LDLs trapped in the arterial intima plays a critical role in atherosclerosis. Though there have been many studies on the atherogenicity of oxidized derivatives of PUFA-esters of cholesterol, the effects of cholesteryl hemiesters (ChEs), the oxidation end products of these esters, have not been studied. Through lipidomics analyses, we identified and quantified two ChE types in the plasma of CVD patients and identified four ChE types in human endarterectomy specimens. Cholesteryl hemiazelate (ChA), the ChE of azelaic acid (n-nonane-1,9-dioic acid), was the most prevalent ChE identified in both cases. Importantly, human monocytes, monocyte-derived macrophages, and neutrophils exhibit inflammatory features when exposed to subtoxic concentrations of ChA in vitro. ChA increases the secretion of proinflammatory cytokines such as interleukin-1ß and interleukin-6 and modulates the surface-marker profile of monocytes and monocyte-derived macrophage. In vivo, when zebrafish larvae were fed with a ChA-enriched diet, they exhibited neutrophil and macrophage accumulation in the vasculature in a caspase 1- and cathepsin B-dependent manner. ChA also triggered lipid accumulation at the bifurcation sites of the vasculature of the zebrafish larvae and negatively impacted their life expectancy. We conclude that ChA behaves as an endogenous damage-associated molecular pattern with inflammatory and proatherogenic properties.
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Aterosclerosis , Pez Cebra , Animales , Humanos , Ésteres del Colesterol , Monocitos , Inflamación , ÉsteresRESUMEN
Leishmania donovani infection of macrophages drives profound changes in the metabolism of both the host macrophage and the parasite, which undergoes different phases of development culminating in replication and propagation. However, the dynamics of this parasite-macrophage cometabolome are poorly understood. In this study, a multiplatform metabolomics pipeline combining untargeted, high-resolution CE-TOF/MS and LC-QTOF/MS with targeted LC-QqQ/MS was followed to characterize the metabolome alterations induced in L. donovani-infected human monocyte-derived macrophages from different donors at 12, 36, and 72 h post-infection. The set of alterations known to occur during Leishmania infection of macrophages, substantially expanded in this investigation, characterized the dynamics of the glycerophospholipid, sphingolipid, purine, pentose phosphate, glycolytic, TCA, and amino acid metabolism. Our results showed that only citrulline, arginine, and glutamine exhibited constant trends across all studied infection time points, while most metabolite alterations underwent a partial recovery during amastigote maturation. We determined a major metabolite response pointing to an early induction of sphingomyelinase and phospholipase activities and correlated with amino acid depletion. These data represent a comprehensive overview of the metabolome alterations occurring during promastigote-to-amastigote differentiation and maturation of L. donovani inside macrophages that contributes to our understanding of the relationship between L. donovani pathogenesis and metabolic dysregulation.
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Leishmania donovani , Leishmaniasis Visceral , Humanos , Leishmania donovani/metabolismo , Macrófagos/metabolismo , Metaboloma , Metabolómica , Aminoácidos/metabolismo , Leishmaniasis Visceral/metabolismo , Leishmaniasis Visceral/parasitologíaRESUMEN
Under perturbing conditions such as infection with Leishmania, a protozoan parasite living within the phagosomes in mammalian macrophages, cellular and organellar structures, and metabolism are dynamically regulated for neutralizing the pressure of parasitism. However, how modulations of the host cell metabolic pathways support Leishmania infection remains unknown. Herein, we report that lipid accumulation heightens the susceptibility of mice to L. donovani infection and promotes resistance to first-line anti-leishmanial drugs. Despite being pro-inflammatory, the in vitro generated uninfected lipid-laden macrophages (LLMs) or adipose-tissue macrophages (ATMs) display lower levels of reactive oxygen and nitrogen species. Upon infection, LLMs secrete higher IL-10 and lower IL-12p70 cytokines, inhibiting CD4+ T cell activation and Th1 response suggesting a key modulatory role for intramacrophage lipid accumulation in anti-leishmanial host defence. We, therefore, examined this causal relationship between lipids and immunomodulation using an in vivo high-fat diet (HFD) mouse model. HFD increased the susceptibility to L. donovani infection accompanied by a defective CD4+ Th1 and CD8+ T cell response. The white adipose tissue of HFD mice displays increased susceptibility to L. donovani infection with the preferential infection of F4/80+ CD11b+ CD11c+ macrophages with higher levels of neutral lipids reserve. The HFD increased resistance to a first-line anti-leishmanial drug associated with a defective adaptive immune response. These data demonstrate that the accumulation of neutral lipids contributes to susceptibility to visceral leishmaniasis hindering host-protective immune response and reducing the efficacy of antiparasitic drug therapies.
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Leishmania donovani , Leishmaniasis Visceral , Animales , Ratones , Leishmaniasis Visceral/tratamiento farmacológico , Inmunidad Adaptativa , Linfocitos T CD8-positivos , Lípidos , Ratones Endogámicos BALB C , MamíferosRESUMEN
Leishmania infection of macrophages results in altered Ras isoforms expression and Toll-like receptor-2 (TLR2) expression and functions. Therefore, we examined whether TLR2 would selectively alter Ras isoforms' expression in macrophages. We observed that TLR2 ligands- Pam3CSK4, peptidoglycan (PGN), and FSL- selectively modulated the expression of Ras isoforms in BALB/c-derived elicited macrophages. Lentivirally-expressed TLR1-shRNA significantly reversed this Ras isoforms expression profile. TLR2-deficient L. major-infected macrophages and the lymph node cells from the L. major-infected mice showed similarly reversed Ras isoforms expression. Transfection of the macrophages with the siRNAs for the adaptors- Myeloid Differentiation factor 88 (MyD88) and Toll-Interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP)- or Interleukin-1 Receptor-Associated Kinases (IRAKs)- IRAK1 and IRAK4- significantly inhibited the L. major-induced down-regulation of K-Ras, and up-regulation of N-Ras and H-Ras, expression. The TLR1/TLR2-ligand Pam3CSK4 increased IL-10 and TGF-ß expression in macrophages. Pam3CSK4 upregulated N-Ras and H-Ras, but down-regulated K-Ras, expression in C57BL/6 wild-type, but not in IL-10-deficient, macrophages. IL-10 or TGF-ß signaling inhibition selectively regulated Ras isoforms expression. These observations indicate the specificity of the TLR2 regulation of Ras isoforms and their selective modulation by MyD88, TIRAP, and IRAKs, but not IL-10 or TGF-ß, signaling.
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Leishmania major , Leishmaniasis Cutánea , Macrófagos , Receptor Toll-Like 2 , Proteínas ras , Leishmaniasis Cutánea/metabolismo , Animales , Ratones , Ratones Endogámicos BALB C , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Macrófagos/metabolismo , Ligandos , Proteínas ras/metabolismo , Peptidoglicano/metabolismo , Quinasas Asociadas a Receptores de Interleucina-1 , Ratones Endogámicos C57BL , Isoformas de Proteínas/metabolismo , Regulación hacia AbajoRESUMEN
Rationale: Sarcoidosis is a multisystemic inflammatory disease characterized by the formation of granulomas in response to persistent stimuli. The long pentraxin PTX3 (pentraxin 3) has emerged as a component of humoral innate immunity with essential functions in the resolution of inflammation, but its role during granuloma formation is unknown. Objectives: To evaluate PTX3 as a modulator of pathogenic signals involved in granuloma formation and inflammation in sarcoidosis. Methods: Peripheral blood mononuclear cells obtained from patients with sarcoidosis harboring loss-of-function genetic variants and gene-deleted mice were used to assess the role of PTX3 in experimental models of granuloma formation in vitro and in vivo. The identified mechanisms of granulomatous inflammation were further evaluated in tissue and BAL samples and correlated with the disease course. Measurements and Main Results: We have identified a molecular link between PTX3 deficiency and the pathogenic amplification of complement activation to promote granuloma formation. Mechanistically, PTX3 deficiency licensed the complement component C5a-mediated activation of the metabolic checkpoint kinase mTORC1 (mammalian target of rapamycin complex 1) and the reprogramming of macrophages toward increased glycolysis to foster their proliferation and aggregation. This process sustained the further recruitment of granuloma-promoting immune cells and the associated proinflammatory microenvironment and influenced the clinical course of the disease. Conclusions: Our results identify PTX3 as a pivotal molecule that regulates complement-mediated signaling cues in macrophages to restrain granulomatous inflammation and highlight the therapeutic potential of this signaling axis in targeting granuloma formation in sarcoidosis.
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Proteína C-Reactiva , Activación de Macrófagos , Sarcoidosis , Componente Amiloide P Sérico , Animales , Ratones , Proteína C-Reactiva/metabolismo , Proteínas del Sistema Complemento , Granuloma , Inflamación , Leucocitos Mononucleares/metabolismo , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo , HumanosRESUMEN
Ovarian cancer metastization is accompanied by the development of malignant ascites, which are associated with poor prognosis. The acellular fraction of this ascitic fluid contains tumor-promoting soluble factors, bioactive lipids, cytokines, and extracellular vesicles, all of which communicate with the tumor cells within this peritoneal fluid. Metabolomic profiling of ovarian cancer ascites has revealed significant differences in the pathways of fatty acids, cholesterol, glucose, and insulin. The proteins involved in these pathways promote tumor growth, resistance to chemotherapy, and immune evasion. Unveiling the key role of this liquid tumor microenvironment is crucial for discovering more efficient treatment options. This review focuses on the cholesterol and insulin pathways in ovarian cancer, identifying statins and metformin as viable treatment options when combined with standard chemotherapy. These findings are supported by clinical trials showing improved overall survival with these combinations. Additionally, statins and metformin are associated with the reversal of T-cell exhaustion, positioning these drugs as potential combinatory strategies to improve immunotherapy outcomes in ovarian cancer patients.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Metformina , Neoplasias Ováricas , Humanos , Femenino , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Metformina/uso terapéutico , Ascitis , Neoplasias Ováricas/tratamiento farmacológico , Insulina , Inmunoterapia , Colesterol , Microambiente TumoralRESUMEN
Leishmania major causes cutaneous leishmaniasis. An antileishmanial vaccine for humans is unavailable. In this study, we report development of two attenuated L. major strains-5ASKH-HP and LV39-HP-by continuous culture (high passage) of the corresponding virulent strains (low passage). Both avirulent strains showed similar changes in proteome profiles when analyzed by surface-enhanced laser desorption ionization mass spectrometry. Liquid chromatography-mass spectrometry and microarray characterization of 5ASKH strains revealed substantially altered gene and protein expression profiles, respectively. Both virulent and avirulent L. major strains grew comparably in culture, but the avirulent strain survived significantly less in BALB/c-derived peritoneal macrophages. Both attenuated strains failed to infect BALB/c mice and elicited IFN-γ, but not IL-4 and IL-10, responses. 5ASKH-HP parasites failed to induce significant infection even in severely immunocompromised- SCID or inducible NO synthase-, CD40-, or IL-12-deficient mice, indicating attenuation. The avirulent strain induced less IL-10, but higher IL-12, in macrophages. The avirulent strain failed to reduce CD40 relocation to the detergent-resistant membrane domain and to inhibit CD40-induced phosphorylation of the kinases Lyn and protein kinase C-ß and MAPKs MKK-3/6 and p38MAPK or to upregulate MEK-1/2 and ERK-1/2 in BALB/c-derived peritoneal macrophages. The virulent and the avirulent strains reciprocally modulated CD40-induced Ras-mediated signaling through PI-3K and Raf-1. Avirulent 5ASKH-primed BALB/c mice were protected against virulent L. major challenge infection. The loss of virulence accompanied by substantially altered proteome profiles and the elicitation of host-protective immune responses indicate plausibly irreversible attenuation of the L. major strain and its potential use as a vaccine strain.
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Antígenos CD40/metabolismo , Leishmania major/fisiología , Vacunas contra la Leishmaniasis/inmunología , Leishmaniasis Cutánea/inmunología , Macrófagos Peritoneales/metabolismo , Animales , Antígenos CD40/genética , Cromatografía Liquida , Citocinas/metabolismo , Humanos , Macrófagos Peritoneales/patología , Espectrometría de Masas , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Transducción de Señal , Transcriptoma , Vacunas Atenuadas , Virulencia , Proteínas ras/metabolismoRESUMEN
This study reports the formulation and delivery of hyaluronic acid-Zein (HA-Zein) nanogels loaded with Shikonin (SK) to selectively attenuate macrophage inflammasome. The self-assembled nanogels, produced by nanoprecipitation, exhibited high encapsulation efficiency, and were selectively internalized by human THP-1-derived macrophages without eliciting cytotoxic responses. Cell treatment with HA-Zein-SK nanogels before stimulation with LPS and Nigericin significantly suppressed caspase-1 activation and IL-1ß production, indicating inflammasome inhibition. Importantly, HA-Zein-SK nanogels bioinstructed inflammasome activated macrophages towards an anti-inflammatory CD163highHLA-DRlow phenotype and led to a marked reduction in the release of pro-inflammatory mediators (TNF-α, IL-6 and IP-10). Extracellular metabolic profiling additionally revealed SK-mediated downregulation of cellular glycolytic activity, which was corroborated by a significant decrease of glycolytic genes transcription. All in all, our findings demonstrate the potential of bioactive SK-containing, self-assembled nanogels to modulate exacerbated responses in innate immune cells and, prospectively, in human tissues where NRLP3 inflammasome is abnormally activated upon injury or disease.
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Inflamasomas , Zeína , Inflamasomas/metabolismo , Interleucina-1beta/genética , Macrófagos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Nanogeles , NaftoquinonasRESUMEN
Ovarian cancer (OC) has a specific type of metastasis, via transcoelomic, and most of the patients are diagnosed at advanced stages with multiple tumors spread within the peritoneal cavity. The role of Malignant Ascites (MA) is to serve as a transporter of tumor cells from the primary location to the peritoneal wall or to the surface of the peritoneal organs. MA comprise cellular components with tumor and non-tumor cells and acellular components, creating a unique microenvironment capable of modifying the tumor behavior. These microenvironment factors influence tumor cell proliferation, progression, chemoresistance, and immune evasion, suggesting that MA play an active role in OC progression. Tumor cells induce a complex immune suppression that neutralizes antitumor immunity, leading to disease progression and treatment failure, provoking a tumor-promoting environment. In this review, we will focus on the High-Grade Serous Carcinoma (HGSC) microenvironment with special attention to the tumor microenvironment immunology.
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Neoplasias Ováricas , Neoplasias Peritoneales , Ascitis/patología , Carcinoma Epitelial de Ovario , Femenino , Humanos , Neoplasias Ováricas/patología , Neoplasias Peritoneales/secundario , Microambiente TumoralRESUMEN
Multiple pathogen-associated molecular patterns (PAMPs) on a pathogen's surface imply their simultaneous recognition by the host cell membrane-located multiple PAMP-specific Toll-like receptors (TLRs). The TLRs on endosomes recognize internalized pathogen-derived nucleic acids and trigger anti-pathogen immune responses aimed at eliminating the intracellular pathogen. Whether the TLRs influence each other's expression and effector responses-termed TLR interdependency-remains unknown. Herein, we first probed the existence of TLR interdependencies and next determined how targeting TLR interdependencies might determine the outcome of Leishmania infection. We observed that TLRs selectively altered expression of their own and of other TLRs revealing novel TLR interdependencies. Leishmania major-an intra-macrophage parasite inflicting the disease cutaneous leishmaniasis in 88 countries-altered this TLR interdependency unfolding a unique immune evasion mechanism. We targeted this TLR interdependency by selective silencing of rationally chosen TLRs and by stimulation with selective TLR ligands working out a novel phase-specific treatment regimen. Targeting the TLR interdependency elicited a host-protective anti-leishmanial immune response and reduced parasite burden. To test whether this observation could be used as a scientific rationale for treating a potentially fatal L. donovani infection, which causes visceral leishmaniasis, we targeted the inter-TLR dependency adopting the same treatment regimen. We observed reduced splenic Leishman-Donovan units accompanied by host-protective immune response in susceptible BALB/c mice. The TLR interdependency optimizes TLR-induced immune response by a novel immunoregulatory framework and scientifically rationalizes targeting TLRs in tandem and in sequence for redirecting immune responses against an intracellular pathogen.
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Leishmania major/fisiología , Leishmaniasis Cutánea/inmunología , Macrófagos/inmunología , Receptores Toll-Like/metabolismo , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Silenciador del Gen , Interacciones Huésped-Parásitos , Humanos , Inmunomodulación , Leishmaniasis Cutánea/terapia , Ratones , Ratones Endogámicos BALB C , Moléculas de Patrón Molecular Asociado a Patógenos/inmunología , ARN Interferente Pequeño/genética , Receptor Cross-Talk , Transducción de Señal , Receptores Toll-Like/genéticaRESUMEN
Cytokines are key mediators of immune responses to autoantigens, tumor antigens and foreign antigens including pathogens and transplant antigens. The cytokines are produced by a variety of immune and non-immune cells and are dynamically regulated. Remarkably, during toxic and septic shock syndromes, anaphylactic shock and in certain viral infections supra-physiologic levels of cytokine storms are produced culminating in multi-organ failure and death. However, Leishmania infection is a chronic parasitic infection with alternate outcomes- healing or non-healing. Leishmania invades macrophages and inflicts the complex of diseases called Leishmaniases. Depending on the species of Leishmania and the organs affected, the diseases are categorized into Cutaneous Leishmaniasis (CL), Muco-cutaneous Leishmaniasis (MCL) and Visceral Leishmaniasis (VL). After successful chemotherapy of VL, a dermal manifestation- termed post-kalazar dermal leishmaniasis (PKDL)- of the same infection occurs in some patients. The operational frameworks for different cytokines have been laid to discuss how these immune mediators control each of these forms of leishmaniases. One of these frameworks is the regulation of monocytopoiesis including the role of macrophages subsets and thrombopoiesis in leishmaniases. Macrophage metabolism is linked to different cytokines and is thereby associated with the manifestation of the resistance or susceptibility to Leishmania infection and of drug resistance. The chemokine-regulated immune cell movements present the landscape of infection and pathogenesis. T cells subsets- the IFN-γ-secreting Ly6Câ¯+â¯T cells and the regulatory T cell subsets- provide the initial skewing of Th cell subset and regulation of effector Th subsets, respectively, eventually deciding the outcome of infection.
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Citocinas/inmunología , Inmunidad/inmunología , Leishmania/inmunología , Leishmaniasis Cutánea/inmunología , Leishmaniasis Visceral/inmunología , Animales , Humanos , Leishmaniasis Cutánea/parasitología , Leishmaniasis Visceral/parasitología , Macrófagos/inmunología , Macrófagos/parasitología , Monocitos/inmunología , Monocitos/parasitología , Subgrupos de Linfocitos T/inmunología , Trombopoyesis/inmunologíaRESUMEN
Leishmania, a protozoan parasite inflicting the complex of diseases called Leishmaniases, resides and replicates as amastigotes within mammalian macrophages. As macrophages are metabolically highly active and can generate free radicals that can destroy this parasite, Leishmania also devise strategies to modulate the host cell metabolism. However, the metabolic changes can also be influenced by the anti-leishmanial immune response mediated by cytokines. This bidirectional, dynamic and complex metabolic coupling established between Leishmania and its host is the result of a long co-evolutionary process. Due to the continuous alterations imposed by the host microenvironment, such metabolic coupling continues to be dynamically regulated. The constant pursuit and competition for nutrients in the host-Leishmania duet alter the host metabolic pathways with major consequences for its nutritional reserves, eventually affecting the phenotype and functionality of the host cell. Altered phenotype and functions of macrophages are particularly relevant to immune cells, as perturbed metabolic fluxes can crucially affect the activation, differentiation, and functions of host immune cells. All these changes can deterministically direct the outcome of an infection. Cytokines and metabolic fluxes can bidirectionally influence each other through molecular sensors and regulators to dictate the final infection outcome. Our studies along with those from others have now identified the metabolic nodes that can be targeted for therapy.
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Citocinas/inmunología , Citocinas/metabolismo , Leishmaniasis/inmunología , Leishmaniasis/metabolismo , Redes y Vías Metabólicas/inmunología , Animales , Interacciones Huésped-Parásitos/inmunología , Humanos , Inmunidad/inmunología , Leishmania/inmunologíaRESUMEN
(a) to analyse the effect of age on physical fitness (PF) and on-duty task (ODT) performance of male police officers (PO); (b) to analyse the relationship between PF and ODT performance of male PO; and (c) to identify the set of PF attributes which better predicts the ODT performance of male PO. A total of 97 Portuguese male non-elite PO (Public Security Police) took part in this cross-sectional study. Participants were allocated to four age categories (20-29, 30-39, 40-49, and >49 years old), and performed fourteen PF evaluations and one on-duty task simulation test (ODT-ST). MANOVA, partial correlations and multiple linear regression analysis were used. We observed (a) a significant decrease of performance with aging (PF attributes, partial eta-squared=0.763; total time on ODT-ST, partial eta-squared=0.498); (b) significant positive associations between body mass index and fat mass with total time on ODT-ST; (c) a significant negative association between standing broad jump (SBJ), sit-up, push-up, bench-press ratio and aerobic capacity with total time on ODT-ST; and (d) that SBJ, abdominal muscular endurance and aerobic capacity were significant predictors of total time on ODT-ST (R2=0.983). PF attributes and ODT performance of Portuguese male non-elite PO decrease significantly with aging. To prevent the observed decrease of performance it seems advisable to implement regular strength and conditioning programmes, which should include muscular power, core strength and aerobic fitness development, to maintain physical capacity and occupational duties.
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[This corrects the article DOI: 10.1371/journal.ppat.1005287.].
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Immunosuppression is a well-established risk factor for Visceral Leishmaniasis. Post-immunosuppression leishmaniasis is characterized by an increase of parasite burden, hematopoietic disorders and unusual clinical manifestations. Although there are many reports on bone marrow findings in VL, less is known about the relationship between parasite dynamics in this organ and the function of either hematopoietic stem cells and progenitor cells themselves. In the present study, we tackle these issues using a new approach of infecting human stem cells derived from bone marrow with L. infantum. Using this strategy, we show that human hematopoietic stem cells (hHSC) are able to phagocytize L. infantum promastigotes and release modulatory and pro-inflammatory cytokines, mainly TNF-α. Our results demonstrated that L. infantum infection in vitro enhances hematopoiesis, favoring the development of erythrocitic lineage through a mechanism yet unknown. Moreover, we found that L. infantum infection alters the phenotypic profile of the hematopoietic progeny; modifying the surface markers expression of differentiated cells. Thus, our study represents a rare opportunity to monitor the in vitro differentiation of human stem cells experimentally infected by L. infantum to better understand the consequences of the infection on phenotypic and functional profile of the cell progeny.
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Diferenciación Celular/inmunología , Eritropoyesis/inmunología , Células Madre Hematopoyéticas/inmunología , Leishmania infantum/inmunología , Fagocitosis/inmunología , Adulto , Anciano , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/parasitología , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/parasitología , Interacciones Huésped-Parásitos/inmunología , Humanos , Leishmania infantum/fisiología , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Leishmaniasis is a vector-borne disease caused by protozoan parasites from the genus Leishmania. The most severe form of disease is visceral leishmaniasis (VL), which is fatal if left untreated. It has been demonstrated that interleukin (IL)-10, is associated with disease progression and susceptibility. In this work, we took advantage of a transgenic mouse model that expresses high levels of IL-10 upon zinc sulfate administration (pMT-10). We addressed the role of IL-10 during the initial stages of L. donovani infection by analyzing the parasite burden in the spleen and liver of the infected pMT-10 and WT mice as well as the histopathological alterations upon IL-10 induction. Furthermore, the profile of cytokines expressed by T cells was assessed. Our results demonstrate that an increase in IL-10 production has an impact early but not later after infection. This specific temporal role for IL-10-mediated susceptibility to VL is of interest.
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Interleucina-10/inmunología , Leishmaniasis Visceral/inmunología , Animales , Leishmania donovani/inmunología , Hígado/inmunología , Hígado/parasitología , Ratones , Ratones Endogámicos C57BL , Bazo/inmunología , Bazo/parasitologíaRESUMEN
Erectile dysfunction (ED) is a complication of diabetes, condition responsible for causing endothelial dysfunction (EDys) and hampering repair mechanisms. However, scarce information is available linking vasculogenesis mediated by Endothelial Progenitor Cells (EPCs) and diabetes-associated ED. Furthermore, it remains to be elucidated if glycemic control plays a role on EPCs functions, EPCs modulators, and penile vascular health. We evaluated the effects of diabetes and insulin therapy on bone marrow (BM) and circulating EPCs, testosterone, and systemic/penile Stromal Derived Factor-1 alpha (SDF-1α) expression. Male Wistar rats were divided into groups: age-matched controls, 8-weeks streptozotocin-induced type 1 diabetics, and insulin-treated 8-weeks diabetics. EPCs were identified by flow cytometry for CD34/CD133/VEGFR2/CXCR4 antigens. Systemic SDF-1α and testosterone levels were evaluated by ELISA. Penile SDF-1α protein expression was assessed, in experimental and human diabetic cavernosal samples, by immunohistochemical techniques. Diabetic animals presented a reduction of BM-derived EPCs and an increase in putative circulating endothelial cells (CECs) sloughed from vessels wall. These alterations were rescued by insulin therapy. In addition, glycemic control promoted an increase in systemic testosterone and SDF-1α levels, which were significantly decreased in animals with diabetes. SDF-1α protein expression was reduced in experimental and human cavernosal diabetic samples, an effect prevented by insulin in treated animals. Insulin administration rescued the effects of diabetes on BM function, CECs levels, testosterone, and plasmatic/penile SDF-1α protein expression. This emphasizes the importance of glycemic control in the prevention of diabetes-induced systemic and penile EDys, by the amelioration of endothelial damage, and increase in protective pathways. J. Cell. Biochem. 118: 82-91, 2017. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Quimiocina CXCL12/sangre , Complicaciones de la Diabetes/sangre , Diabetes Mellitus Experimental/sangre , Impotencia Vasculogénica/sangre , Testosterona/sangre , Animales , Complicaciones de la Diabetes/terapia , Diabetes Mellitus Experimental/terapia , Impotencia Vasculogénica/prevención & control , Masculino , Ratas , Ratas WistarRESUMEN
Metabolic manipulation of host cells by intracellular pathogens is currently recognized to play an important role in the pathology of infection. Nevertheless, little information is available regarding mitochondrial energy metabolism in Leishmania infected macrophages. Here, we demonstrate that during L. infantum infection, macrophages switch from an early glycolytic metabolism to an oxidative phosphorylation, and this metabolic deviation requires SIRT1 and LKB1/AMPK. SIRT1 or LBK1 deficient macrophages infected with L. infantum failed to activate AMPK and up-regulate its targets such as Slc2a4 and Ppargc1a, which are essential for parasite growth. As a result, impairment of metabolic switch caused by SIRT1 or AMPK deficiency reduces parasite load in vitro and in vivo. Overall, our work demonstrates the importance of SIRT1 and AMPK energetic sensors for parasite intracellular survival and proliferation, highlighting the modulation of these proteins as potential therapeutic targets for the treatment of leishmaniasis.