RESUMEN

Inflammation plays a pivotal role in the pathogenesis of primary and post-essential thrombocythemia or post-polycythemia vera myelofibrosis (MF) in close cooperation with the underlying molecular drivers. This inflammatory state is induced by a dynamic spectrum of inflammatory cytokines, although recent evidence points to the participation of additional soluble inflammatory mediators. Damage-associated molecular patterns (DAMPs) represent endogenous signals released upon cell death or damage which trigger a potent innate immune response. We assessed the contribution of two prototypical DAMPs, HMGB1 and S100A8/A9, to MF inflammation. Circulating HMGB1 and S100A8/A9 were elevated in MF patients in parallel to the degree of systemic inflammation and levels increased progressively during advanced disease stages. Patients with elevated DAMPs had higher frequency of adverse clinical features, such as anemia, and inferior survival, suggesting their contribution to disease progression. Monocytes, which are key players in MF inflammation, were identified as a source of S100A8/A9 but not HMGB1 release, while both DAMPs correlated with cell death parameters, such as serum LDH and cell-free DNA, indicating that passive release is an additional mechanism leading to increased DAMPs. HMGB1 and S100A8/A9 promote inflammation through binding to Toll-like receptor (TLR) 4, whereas the former also binds TLR2. Monocytes from MF patients were shown to be hyperactivated at baseline, as reflected by higher CD11b and tissue factor exposure and increased expression levels of proinflammatory cytokines IL-1ß and IL-6. Patient monocytes showed preserved TLR4 and TLR2 expression and were able to mount normal or even exacerbated functional responses and cytokine upregulation following stimulation of TLR4 and TLR2. Elevated levels of endogenous TLR ligands HMGB1 and S100A8/A9 coupled to the finding of preserved or hyperreactive TLR-triggered responses indicate that DAMPs may promote monocyte activation and cytokine production in MF, fueling inflammation. Plasma IL-1ß and IL-6 were elevated in MF and correlated with DAMPs levels, raising the possibility that DAMPs could contribute to cytokine generation in vivo. In conclusion, this study highlights that, in cooperation with classic proinflammatory cytokines, DAMPs represent additional inflammatory mediators that may participate in the generation of MF inflammatory state, potentially providing novel biomarkers of disease progression and new therapeutic targets.

Asunto(s)

Alarminas , Calgranulina A , Calgranulina B , Proteína HMGB1 , Inflamación , Monocitos , Mielofibrosis Primaria , Humanos , Proteína HMGB1/sangre , Proteína HMGB1/metabolismo , Calgranulina A/sangre , Calgranulina B/sangre , Masculino , Femenino , Monocitos/inmunología , Monocitos/metabolismo , Anciano , Persona de Mediana Edad , Alarminas/metabolismo , Alarminas/inmunología , Inflamación/inmunología , Mielofibrosis Primaria/inmunología , Mielofibrosis Primaria/metabolismo , Anciano de 80 o más Años , Receptores Toll-Like/metabolismo , Citocinas/metabolismo , Adulto , Receptor Toll-Like 4/metabolismo , Biomarcadores

RESUMEN

INTRODUCTION: In X-linked agammaglobulinemia (XLA), the diversity of BTK variants complicates the study of genotype-phenotype correlations. Since BTK negatively regulates toll-like receptors (TLRs), we investigated if distinct BTK mutation types selectively modulate TLR pathways, affecting disease expression. METHODS: Using reverse transcription-quantitative polymerase chain reaction, we quantified ten TLR signaling-related genes in XLA patients with missense (n = 3) and nonsense (n = 5) BTK mutations and healthy controls (n = 17). RESULTS: BTK, IRAK2, PIK3R4, REL, TFRC, and UBE2N were predominantly downregulated, while RIPK2, TLR3, TLR10, and TLR6 showed variable regulation. The missense XLA group exhibited significant downregulation of IRAK2, PIK3R4, REL, and TFRC and upregulation of TLR3 and/or TLR6. CONCLUSION: Hypo-expression of TLR3, TLR6, and TLR10 may increase susceptibility to infections, while hyper-expression might contribute to chronic inflammatory conditions like arthritis or inflammatory bowel disease. Our findings shed light on the important inflammatory component characteristic of some XLA patients, even under optimal therapeutic conditions.

Asunto(s)

Agammaglobulinemia Tirosina Quinasa , Agammaglobulinemia , Estudios de Asociación Genética , Enfermedades Genéticas Ligadas al Cromosoma X , Transducción de Señal , Receptores Toll-Like , Humanos , Agammaglobulinemia/genética , Agammaglobulinemia/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Agammaglobulinemia Tirosina Quinasa/genética , Transducción de Señal/genética , Masculino , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Adolescente , Niño , Regulación de la Expresión Génica , Adulto , Preescolar , Adulto Joven , Femenino , Mutación

RESUMEN

Natural killer (NK) cells play a crucial role in innate immunity, particularly in combating infections and tumors. However, in hematological cancers, NK cells often exhibit impaired functions. Therefore, it is very important to activate its endosomal Toll-like receptors (TLRs) as a potential strategy to restore its antitumor activity. We stimulated NK cells from the peripheral blood mononuclear cells from children with acute lymphoblastic leukemia and NK cells isolated, and the NK cells were stimulated with specific TLR ligands (Poly I:C, Imiquimod, R848, and ODN2006) and we evaluated changes in IFN-γ, CD107a, NKG2D, NKp44 expression, Granzyme B secretion, cytokine/chemokine release, and cytotoxic activity. Results revealed that Poly I:C and Imiquimod enhanced the activation of both immunoregulatory and cytotoxic NK cells, increasing IFN-γ, CD107a, NKG2D, and NKp44 expression. R848 activated immunoregulatory NK cells, while ODN2006 boosted CD107a, NKp44, NKG2D, and IFN-γ secretion in cytotoxic NK cells. R848 also increased the secretion of seven cytokines/chemokines. Importantly, R848 and ODN 2006 significantly improved cytotoxicity against leukemic cells. Overall, TLR stimulation enhances NK cell activation, suggesting TLR8 (R848) and TLR9 (ODN 2006) ligands as promising candidates for antitumor immunotherapy.

Asunto(s)

Imiquimod , Células Asesinas Naturales , Activación de Linfocitos , Poli I-C , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores Toll-Like , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Poli I-C/farmacología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Imiquimod/farmacología , Receptores Toll-Like/metabolismo , Receptores Toll-Like/agonistas , Niño , Oligodesoxirribonucleótidos/farmacología , Citocinas/metabolismo , Femenino , Interferón gamma/metabolismo , Masculino , Imidazoles/farmacología , Citotoxicidad Inmunológica/efectos de los fármacos , Preescolar , Agonistas de los Receptores Toll-Like

RESUMEN

Toll-like receptors (TLRs) are among the main components of the innate immune system. They can detect conserved structures in microorganisms and molecules associated with stress and cellular damage. TLRs are expressed in resident immune cells and both neurons and glial cells of the nervous system. Increasing evidence is emerging on the participation of TLRs not only in the immune response but also in processes of the nervous system, such as neurogenesis and cognition. Below, we present a review of the literature that evaluates the expression and role of TLRs in processes such as neurodevelopment, behavior, cognition, infection, neuroinflammation, and neurodegeneration.

Asunto(s)

Sistema Nervioso , Neurogénesis , Receptores Toll-Like , Humanos , Receptores Toll-Like/metabolismo , Animales , Sistema Nervioso/metabolismo , Sistema Nervioso/inmunología , Inmunidad Innata , Neuronas/metabolismo , Neuronas/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/inmunología , Transducción de Señal

RESUMEN

OBJECTIVES: The pathogenic mechanisms of Thromboangiitis Obliterans (TAO) are not entirely known and autoimmune inflammation plays a vital role in the initiation and continuance of TAO activity. The authors investigated in this study the role of the TLR signaling pathway in the pathogenesis of TAO. METHODS: First, the authors detected the expressions of MyD88, TRIF and NF-κB in vascular walls of 46 patients with TAO and 32 patients with trauma and osteosarcoma by western blot assay. Second, the authors detected the cellular localization of MyD88, TRIF and NF-κB in vascular walls of patients with TAO by immunofluorescent assay. RESULTS: The protein expressions of MyD88, TRIF and NF-κB were much higher in vascular walls of TAO patients (p < 0.05). Higher expressions of MyD88 and NF-κB were detected both on vascular endothelial and vascular smooth muscle cells of TAO patients. However, higher expression of TRIF was just detected on vascular smooth muscle cells of TAO patients. CONCLUSIONS: These dates suggest that the TLR signaling pathway might play an important role in the pathogenesis of TAO, it might induce vasospasm, vasculitis and thrombogenesis to lead to the pathogenesis and progression of TAO.

Asunto(s)

Proteínas Adaptadoras del Transporte Vesicular , Factor 88 de Diferenciación Mieloide , FN-kappa B , Transducción de Señal , Tromboangitis Obliterante , Receptores Toll-Like , Humanos , Tromboangitis Obliterante/metabolismo , FN-kappa B/metabolismo , Transducción de Señal/fisiología , Masculino , Receptores Toll-Like/metabolismo , Femenino , Adulto , Factor 88 de Diferenciación Mieloide/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Persona de Mediana Edad , Western Blotting , Adulto Joven , Músculo Liso Vascular/metabolismo , Adolescente , Estudios de Casos y Controles

RESUMEN

Dental tissue stem cells (DTSCs) are well known for their multipotent capacity and regenerative potential. They also play an important role in the immune response of inflammatory processes derived from caries lesions, periodontitis, and gingivitis. These oral diseases are triggered by toxins known as lipopolysaccharides (LPS) produced by gram-negative bacteria. LPS present molecular patterns associated with pathogens and are recognized by Toll-like receptors (TLRs) in dental stem cells. In this review, we describe the effect of LPS on the biological behavior of DTSCs. We also focus on the molecular sensors, signaling pathways, and emerging players participating in the interaction of DTSCs with lipopolysaccharides. Although the scientific advances generated provide an understanding of the immunomodulatory potential of DTSCs, there are still new reflections to explore with regard to their clinical application in the treatment of oral inflammatory diseases.

Asunto(s)

Pulpa Dental , Lipopolisacáridos , Células Madre , Animales , Humanos , Pulpa Dental/citología , Pulpa Dental/metabolismo , Lipopolisacáridos/metabolismo , Transducción de Señal , Células Madre/metabolismo , Receptores Toll-Like/metabolismo , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/metabolismo

RESUMEN

Herpes simplex virus 1 (HSV-1) or simplexvirus humanalpha 1 is a neurotropic virus that is responsible for orofacial infections in humans. More than 70% of the world's population may have seropositivity for HSV-1, and this virus is a leading cause of sporadic lethal encephalitis in humans. The role of toll-like receptors (TLRs) in defending against HSV-1 infection has been explored, including the consequences of lacking these receptors or other proteins in the TLR pathway. Cell and mouse models have been used to study the importance of these receptors in combating HSV-1, how they relate to the innate immune response, and how they participate in the orchestration of the adaptive immune response. Myeloid differentiation factor 88 (MyD88) is a protein involved in the downstream activation of TLRs and plays a crucial role in this signaling. Mice with functional MyD88 or TLR2 and TLR9 can survive HSV-1 infection. However, they can develop encephalitis and face a 100% mortality rate in a dose-dependent manner when MyD88 or TLR2 plus TLR9 proteins are non-functional. In TLR2/9 knockout mice, an increase in chemokines and decreases in nitric oxide (NO), interferon (IFN) gamma, and interleukin 1 (IL-1) levels in the trigeminal ganglia (TG) have been correlated with mortality.

Asunto(s)

Encefalitis , Herpes Simple , Herpesvirus Humano 1 , Humanos , Animales , Ratones , Herpesvirus Humano 1/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Ganglio del Trigémino/metabolismo , Receptores Toll-Like/metabolismo , Ratones Noqueados , Ratones Endogámicos C57BL

RESUMEN

Methadone is an effective and long-lasting analgesic drug that is also used in medication-assisted treatment for people with opioid use disorders. Although there is evidence that methadone activates µ-opioid and Toll-like-4 receptors (TLR-4s), its effects on distinct immune cells, including mast cells (MCs), are not well characterized. MCs express µ-opioid and Toll-like receptors (TLRs) and constitute an important cell lineage involved in allergy and effective innate immunity responses. In the present study, murine bone-marrow-derived mast cells (BMMCs) were treated with methadone to evaluate cell viability by flow cytometry, cell morphology with immunofluorescence and scanning electron microscopy, reactive oxygen species (ROS) production, and intracellular calcium concentration ([Ca2+]i) increase. We found that exposure of BMMCs to 0.5 mM or 1 mM methadone rapidly induced cell death by forming extracellular DNA traps (ETosis). Methadone-induced cell death depended on ROS formation and [Ca2+]i. Using pharmacological approaches and TLR4-defective BMMC cultures, we found that µ-opioid receptors were necessary for both methadone-induced ROS production and intracellular calcium increase. Remarkably, TLR4 receptors were also involved in methadone-induced ROS production as it did not occur in BMMCs obtained from TLR4-deficient mice. Finally, confocal microscopy images showed a significant co-localization of µ-opioid and TLR4 receptors that increased after methadone treatment. Our results suggest that methadone produces MCETosis by a mechanism requiring a novel crosstalk pathway between µ-opioid and TLR4 receptors.

Asunto(s)

Analgésicos Opioides , Trampas Extracelulares , Humanos , Animales , Ratones , Analgésicos Opioides/farmacología , Receptor Toll-Like 4/metabolismo , Metadona/farmacología , Mastocitos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Médula Ósea/metabolismo , Calcio/metabolismo , Trampas Extracelulares/metabolismo , Receptor Toll-Like 2/metabolismo , Receptores Toll-Like/metabolismo

RESUMEN

BACKGROUND: Multiple blood cell abnormalities participate in the development of inflammation in systemic lupus erythematosus (SLE). Although platelets have been suggested as one of these contributors through the release of their content during activation, there are limited specific data about their role as immune players in SLE. MATERIALS AND METHODS: Thirteen SLE patients were included. Flow cytometry was used to measure Toll-like receptors (TLR) 2, 4, and 9 in resting platelets, platelet-activation markers (PAC-1 binding, P-selectin, CD63, and CD40 ligand -L) and platelet-leukocyte aggregates before and after specific TLR stimulation. Soluble CD40L and von Willebrand factor (vWf) release from stimulated platelets was measured using ELISA. RESULTS: In resting conditions, SLE platelets showed normal expression levels of TLR 2, 4 and 9. Platelet surface activation markers, soluble CD40L, and vWf release were normal at baseline and after TLR stimulation. Platelet-monocyte aggregates were elevated in resting conditions in SLE samples and showed only a marginal increase after TLR stimulation, while baseline and stimulated platelet-neutrophil and platelet-lymphocyte aggregates were normal. C-reactive protein levels positively correlated with platelet-monocyte aggregates both at baseline and after stimulation with the TLR-2 agonist PAM3CSK4, suggesting these complexes could reflect the inflammatory activity in SLE. In our cohort, 12 of 13 patients received treatment with hydroxychloroquine (HCQ), a known inhibitor of endosomal activity and a potential inhibitor of platelet activation. The fact that SLE platelets showed an adequate response to TLR agonists suggests that, despite this treatment, they retain the ability to respond to the increased levels of damage-associated molecular patterns (DAMPs), which represent known TLR ligands, present in the circulation of SLE patients. Interestingly, elevated plasma levels of high mobility group box 1 (HMGB1), a classical DAMP, correlated with vWf release from TLR-stimulated platelets, suggesting that HMGB1 may also be released by platelets, thereby creating a positive feedback loop for platelet activation that contributes to inflammation. CONCLUSION: Our study demonstrates normal platelet TLR expression and function together with increased circulating platelet-monocyte aggregates. In addition, a direct correlation was observed between plasma HMGB1 levels and platelet vWf release following TLR2 stimulation. This platelet behavior in a group of patients undergoing HCQ treatment suggests that platelets could play a role in the inflammatory state of SLE.

Asunto(s)

Proteína HMGB1 , Lupus Eritematoso Sistémico , Humanos , Proteína HMGB1/metabolismo , Ligando de CD40 , Factor de von Willebrand/metabolismo , Receptores Toll-Like/metabolismo , Plaquetas/metabolismo , Inflamación/metabolismo , Receptor Toll-Like 9

RESUMEN

There is evidence that the administration of ß-glucan can effectively activate several defense mechanisms, such as the Tlr-Myd88-Nfkb1 pathway that induces the expression of immune cytokines. Thus, the objective of this work was to evaluate whether ß-glucan acts on the mechanisms of gene transcription via the Tlr-Myd88-Nfkb1 pathway in Nile tilapia under stress after challenge with Streptococcus agalactiae. Therefore, we evaluated the expression of immune system genes such as toll-like receptors 1 (tlr1), toll-like receptors 2 (tlr2), primary myeloid differentiation response gene (myd88) and nuclear factor kappa B1 (nfkb1). A total of 408 fish were distributed in 24 polyethylene boxes and randomly divided into eight groups with 3 replications each: C15: Tilapias received a control diet (free of ß-glucan) for 15 days and were sampled after the 15th day of the experiment; C15D: Tilapias received a control diet (free of ß-glucan) for 15 days, were challenged on the 14th day and were sampled at the 15th day of the experiment; ß15: Tilapias received experimental diet (1g kg-1 of ß-glucan) for 15 days and were sampled after 15 days; ß15D: Tilapias received an experimental diet (1g kg-1 of ß-glucan) for 15 days, were challenged on the 14th day and were sampled at the 15th day of the experiment; C30: Tilapias received a control diet (free of ß-glucan) for 30 days and were sampled on the 30th day of the experiment; C30D: Tilapias received a control diet (free of ß-glucan) for 30 days, were challenged on the 29th day and were sampled at the 30th day of the experiment; ß30: Tilapias received experimental diet (1g kg-1 of ß-glucan) for 30 days and were sampled after 30 days and ß30D: Tilapias received experimental diet (1g kg-1 of ß-glucan) for 30 days, were challenged on the 29th day and were sampled at 30 of the experiment. In the fish sampled at 15 and 30 days of the experiment, after being anesthetized and killed by brain section, cranial kidney and spleen were collected for gene expression analysis. The analyzes showed that the association of ß-glucan and stressful management modulated the immune system, using the Tlr-Myd88-Nfkb1 signaling pathway, indicating that this compound can be used to promote early defense and protect fish against diseases.

Asunto(s)

Cíclidos , Enfermedades de los Peces , beta-Glucanos , Animales , beta-Glucanos/farmacología , beta-Glucanos/metabolismo , Suplementos Dietéticos , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Dieta/veterinaria , Transducción de Señal , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Alimentación Animal/análisis

RESUMEN

Worldwide, gastric cancer (GC) is the fifth most commonly diagnosed malignancy. It has a reduced prevalence but has maintained its poor prognosis being the fourth leading cause of deaths related to cancer. The highest mortality rates occur in Asian and Latin American countries, where cases are usually diagnosed at advanced stages. Overall, GC is viewed as the consequence of a multifactorial process, involving the virulence of the Helicobacter pylori (H. pylori) strains, as well as some environmental factors, dietary habits, and host intrinsic factors. The tumor microenvironment in GC appears to be chronically inflamed which promotes tumor progression and reduces the therapeutic opportunities. It has been suggested that inflammation assessment needs to be measured qualitatively and quantitatively, considering cell-infiltration types, availability of receptors to detect damage and pathogens, and presence or absence of aggressive H. pylori strains. Gastrointestinal epithelial cells express several Toll-like receptors and determine the first defensive line against pathogens, and have been also described as mediators of tumorigenesis. However, other molecules, such as cytokines related to inflammation and innate immunity, including immune checkpoint molecules, interferon-gamma pathway and NETosis have been associated with an increased risk of GC. Therefore, this review will explore innate immune activation in the context of premalignant lesions of the gastric epithelium and established gastric tumors.

Asunto(s)

Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/metabolismo , Inmunidad Innata , Citocinas/metabolismo , Inflamación/metabolismo , Receptores Toll-Like/metabolismo , Mucosa Gástrica/metabolismo , Microambiente Tumoral

RESUMEN

The engagement of B cells with surface-tethered antigens triggers the formation of an immune synapse (IS), where the local secretion of lysosomes can facilitate antigen uptake. Lysosomes intersect with other intracellular processes, such as Toll-like Receptor (TLR) signaling and autophagy coordinating immune responses. However, the crosstalk between these processes and antigen presentation remains unclear. Here, we show that TLR stimulation induces autophagy in B cells and decreases their capacity to extract and present immobilized antigens. We reveal that TLR stimulation restricts lysosome repositioning to the IS by triggering autophagy-dependent degradation of GEF-H1, a Rho GTP exchange factor required for stable lysosome recruitment at the synaptic membrane. GEF-H1 degradation is not observed in B cells that lack αV integrins and are deficient in TLR-induced autophagy. Accordingly, these cells show efficient antigen extraction in the presence of TLR stimulation, confirming the role of TLR-induced autophagy in limiting antigen extraction. Overall, our results suggest that resources associated with autophagy regulate TLR and BCR-dependent functions, which can finetune antigen uptake by B cells. This work helps to understand the mechanisms by which B cells are activated by surface-tethered antigens in contexts of subjacent inflammation before antigen recognition, such as sepsis.

Asunto(s)

Linfocitos B , Receptores de Antígenos de Linfocitos B , Receptores de Antígenos de Linfocitos B/metabolismo , Antígenos/metabolismo , Receptores Toll-Like/metabolismo , Autofagia , Antígenos de Superficie/metabolismo , Factores de Intercambio de Guanina Nucleótido Rho/metabolismo

RESUMEN

Systemic lupus erythematosus (SLE) is a heterogeneous, multisystemic autoimmune disease with a broad clinical spectrum. Loss of self-tolerance and chronic inflammation are critical markers of SLE pathogenesis. Although alterations in adaptive immunity are widely recognized, increasing reports indicate the role of mitochondrial dysfunction in activating pathogenic pathways involving the innate immune system. Among these, disarrangements in mitochondrial DNA copy number and heteroplasmy percentage are related to SLE activity. Furthermore, increased oxidative stress contributes to post-translational changes in different molecules (proteins, nucleic acids, and lipids), release of oxidized mitochondrial DNA through a pore of voltage-dependent anion channel oligomers, and spontaneous mitochondrial antiviral signaling protein oligomerization. Finally, a reduction in mitophagy, apoptosis induction, and NETosis has been reported in SLE. Most of these pathways lead to persistent and inappropriate exposure to oxidized mitochondrial DNA, which can stimulate plasmacytoid dendritic cells, enhance autoreactive lymphocyte activation, and release increased amounts of interferons through stimulation of toll-like receptors and cytosolic DNA sensors. Likewise, abnormal T-cell receptor activation, decreased regulatory T cells, enhanced Th17 phenotypes, and increased monocyte maturation to dendritic cells have also been observed in SLE. Targeting the players involved in mitochondrial damage can ultimately help.

Asunto(s)

Lupus Eritematoso Sistémico , Antivirales/metabolismo , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Humanos , Interferones/metabolismo , Lípidos , Mitocondrias/genética , Mitocondrias/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Toll-Like/metabolismo

RESUMEN

Literature shows that phospholipases A2 isolated from snake venoms of the genus Bothrops are involved in the local inflammatory response. However, the mechanisms by which these enzymes trigger this process have not yet been clarified. Toll-Like receptors (TLRs) are transmembrane proteins that recognize pathogens associated molecular patterns (PAMPs), or even damage associated molecular patterns (DAMPs). After this recognition, an innate immune response is activated resulting in cytokines liberation contributing to inflammation. Thus, the purpose of this work was to study the participation of different TLRs during the local inflammatory process induced by B. jararacussu snake venom and by two isolated phospholipases A2, BthTX-I or BthTX-II, from this venom in a model of experimental envenoming. For this, sub-lethal doses of B. jararacussu venom (BjussuV), BthTX-I or BthTX-II were injected in the gastrocnemius muscle. Myotoxic activity was evaluated by histological analysis and by quantification of plasma levels of total-creatine kinase (CK). The pro-inflammatory cytokines TNF-α and IL-1ß was measured in both muscle tissue homogenate and plasma. A quantification of the gene expression of TLRs 2, 4, 5 and 9 in muscle tissue homogenate was performed by the real-time polymerase chain reaction (RTq-PCR). According to the results, it can be observed that, when compared to the control, there was a significant increase of CK and TNF-α in the bloodstream of the animals injected with both BjussuV, BthTX-I and BthTX-II. In muscle tissue homogenate, it was observed a significant increase in both cytokines, TNF-α and IL-1ß, levels compared to the control animals. The results point to an important increase in the gene expression of TLR2 and TLR4, suggesting that these TLRs can be important targets for the development of future therapies for local treatment for victims of snakebites.

Asunto(s)

Bothrops , Venenos de Crotálidos , Animales , Bothrops/metabolismo , Creatina Quinasa , Músculo Esquelético , Fosfolipasas A2/metabolismo , Receptores Toll-Like/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

A therapeutic strategy for prostate cancer (PCa) involves the use of 9-cis-retinoic acid (9cRA) to induce cancer stem cells (CSCs) differentiation and apoptosis. Polyinosinic:polycytidylic acid (PIC) is a Toll-like receptor 3 (TLR3) agonist that induces tumor cells apoptosis after activation. PIC+9cRA combination activates retinoic acid receptor ß (RARß) re-expression, leading to CSC differentiation and growth arrest. Since inorganic arsenic (iAs) targets prostatic stem cells (SCs), we hypothesized that arsenic-transformed SCs (As-CSCs) show an impaired TLR3-associated anti-tumor pathway and, therefore, are unresponsive to PIC activation. We evaluated TLR3-mediated activation of anti-tumor pathway based in RARß expression, on As-CSC and iAs-transformed epithelial cells (CAsE-PE). As-CSCs and CAsE-PE showed lower TLR3 and RARß basal expression compared to their respective isogenic controls WPE-Stem and RWPE-1. Also, iAs transformants showed reduced expression of mediators in TLR3 pathway. Importantly, As-CSCs were irresponsive to PIC+9cRA in terms of increased RARß and decreased SC-markers expression, while CAsE-PE, a heterogeneous cell line having a small SC population, were partially responsive. These observations indicate that iAs can impair TLR3 expression and anti-tumor pathway activated by PIC+9cRA in SCs and prostatic epithelial cells. These findings suggest that TLR3-activation based therapy may be an ineffective therapeutic alternative for iAs-associated PCa.

Asunto(s)

Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Compuestos de Sodio/toxicidad , Receptores Toll-Like/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Células Cultivadas/efectos de los fármacos , Células Cultivadas/metabolismo , Variación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Próstata/efectos de los fármacos , Próstata/metabolismo , Neoplasias de la Próstata/fisiopatología , Compuestos de Sodio/metabolismo , Receptores Toll-Like/metabolismo

RESUMEN

BACKGROUND: Arthropoda, the most numerous and diverse metazoan phylum, has species in many habitats where they encounter various microorganisms and, as a result, mechanisms for pathogen recognition and elimination have evolved. The Toll pathway, involved in the innate immune system, was first described as part of the developmental pathway for dorsal-ventral differentiation in Drosophila. Its later discovery in vertebrates suggested that this system was extremely conserved. However, there is variation in presence/absence, copy number and sequence divergence in various genes along the pathway. As most studies have only focused on Diptera, for a comprehensive and accurate homology-based approach it is important to understand gene function in a number of different species and, in a group as diverse as insects, the use of species belonging to different taxonomic groups is essential. RESULTS: We evaluated the diversity of Toll pathway gene families in 39 Arthropod genomes, encompassing 13 different Insect Orders. Through computational methods, we shed some light into the evolution and functional annotation of protein families involved in the Toll pathway innate immune response. Our data indicates that: 1) intracellular proteins of the Toll pathway show mostly species-specific expansions; 2) the different Toll subfamilies seem to have distinct evolutionary backgrounds; 3) patterns of gene expansion observed in the Toll phylogenetic tree indicate that homology based methods of functional inference might not be accurate for some subfamilies; 4) Spatzle subfamilies are highly divergent and also pose a problem for homology based inference; 5) Spatzle subfamilies should not be analyzed together in the same phylogenetic framework; 6) network analyses seem to be a good first step in inferring functional groups in these cases. We specifically show that understanding Drosophila's Toll functions might not indicate the same function in other species. CONCLUSIONS: Our results show the importance of using species representing the different orders to better understand insect gene content, origin and evolution. More specifically, in intracellular Toll pathway gene families the presence of orthologues has important implications for homology based functional inference. Also, the different evolutionary backgrounds of Toll gene subfamilies should be taken into consideration when functional studies are performed, especially for TOLL9, TOLL, TOLL2_7, and the new TOLL10 clade. The presence of Diptera specific clades or the ones lacking Diptera species show the importance of overcoming the Diptera bias when performing functional characterization of Toll pathways.

Asunto(s)

Factor 88 de Diferenciación Mieloide , Receptores Toll-Like , Animales , Evolución Molecular , Factor 88 de Diferenciación Mieloide/genética , Filogenia , Transducción de Señal , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo

RESUMEN

Toll-like receptors (TLRs) are a family of transmembrane receptors whose signaling control cellular processes of cell proliferation, survival, apoptosis, angiogenesis, remodeling, and repair of tissues. Polymorphisms in TLR genes can change the balance between pro and anti-inflammatory cytokines, modulating the risk of infection, chronic inflammation, and cancer. Although many studies have demonstrated the direct involvement of TLR signaling in the benefit of tumor cells in certain cancers, little is known about the influence of these gene polymorphisms on myeloproliferative neoplasms (MPNs). In this context, the objective of the study was to investigate a possible association between the TLR polymorphisms and the development of MPNs. 167 patients diagnosed with MPN and 222 healthy controls from the same region were evaluated. Genomic DNA was extracted and the TLR2 (rs5743708), TLR4 (rs4986790, rs4986791), TLR9 (rs5743836, rs187084) and JAK2V617F polymorphisms were genotyped by PCR-RFLP. The statistical analysis was performed by OpenEpi and SNPstat software. The JAK2V617F mutation was found in 68.32% of patients. TLR9-1486C/T CT genotype was less frequent in patients with polycythemia vera (PV) (OR 0.39, 95% CI 0.20-0.78, P = 0.025). When haplotype frequencies were analyzed, -1237T/-1486C (TLR9) was also less frequent in men (OR 0.58, 95% CI 0.36-0.94) and JAK negative men patients (OR 0.43, 95% CI 0.21-0.88). We can infer that the TLR9-1486 CT genotype could be associated with protection for PV and the TLR9-1237T/-1486C haplotype, protection for men, as well as for JAK negative men patients with MPN. There were no associations between TLR2 and TLR4 gene polymorphisms and MPN.

Asunto(s)

Neoplasias de la Médula Ósea/genética , Janus Quinasa 2/genética , Receptor Toll-Like 9/genética , Receptores Toll-Like/genética , Adulto , Anciano , Neoplasias de la Médula Ósea/metabolismo , Femenino , Haplotipos/genética , Humanos , Janus Quinasa 2/metabolismo , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/genética , Policitemia Vera/genética , Polimorfismo de Nucleótido Simple/genética , Mielofibrosis Primaria/genética , Trombocitemia Esencial/genética , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 9/metabolismo , Receptores Toll-Like/metabolismo

RESUMEN

INTRODUCTION: The pathogen-associated molecular patterns and the danger-associated molecular patterns are possibly responsible for the activation of the inflammatory process in endometriosis through the activation of toll-like receptors (TLRs). OBJECTIVE: The aim of this systematic review was to critically analyze the findings of published articles on TLRs in endometriosis. METHODS: The keywords used were "endometriosis" and "toll-like" and the search was performed in Pubmed, Scielo and Lilacs databases. This study followed the PRISMA guidelines and the risk of bias of articles was conducted by Newcastle-Ottawa scale (NOS). RESULTS: Overall, the studies analyzed in this review point toward an increased expression of TLRs two, four and nine in women with endometriosis. Among all TLRs, TLR4 was the most cited receptor. CONCLUSION: Despite the evidence demonstrating elevated TLR levels in endometriosis, the relationship with the disease is still unclear and needs to be clarified in further studies about innate immune response.

Asunto(s)

Endometriosis/metabolismo , Receptores Toll-Like/metabolismo , Femenino , Humanos , Inmunidad Innata

RESUMEN

Psychostimulant use is a major comorbidity in people living with HIV, which was initially explained by them adopting risky behaviors that facilitate HIV transmission. However, the effects of drug use on the immune system might also influence this phenomenon. Psychostimulants act on peripheral immune cells even before they reach the central nervous system (CNS) and their effects on immunity are likely to influence HIV infection. Beyond their canonical activities, classic neurotransmitters and neuromodulators are expressed by peripheral immune cells (e.g., dopamine and enkephalins), which display immunomodulatory properties and could be influenced by psychostimulants. Immune receptors, like Toll-like receptors (TLRs) on microglia, are modulated by cocaine and amphetamine exposure. Since peripheral immunocytes also express TLRs, they may be similarly affected by psychostimulants. In this review, we will summarize how psychostimulants are currently thought to influence peripheral immunity, mainly focusing on catecholamines, enkephalins and TLR4, and shed light on how these drugs might affect HIV infection. We will try to shift from the classic CNS perspective and adopt a more holistic view, addressing the potential impact of psychostimulants on the peripheral immune system and how their systemic effects could influence HIV infection.

Asunto(s)

Enfermedades Transmisibles/etiología , Susceptibilidad a Enfermedades , Interacciones Huésped-Patógeno/efectos de los fármacos , Interacciones Huésped-Patógeno/inmunología , Sistema Inmunológico/efectos de los fármacos , Animales , Biomarcadores , Estimulantes del Sistema Nervioso Central/efectos adversos , Enfermedades Transmisibles/epidemiología , Enfermedades Transmisibles/metabolismo , Susceptibilidad a Enfermedades/inmunología , Infecciones por VIH/etiología , Infecciones por VIH/metabolismo , Humanos , Inmunidad/efectos de los fármacos , Inmunomodulación , Vigilancia de la Población , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Receptores Toll-Like/metabolismo

RESUMEN

COVID-19 is a pandemic disease caused by a coronavirus, designed as SARS CoV-2, whose clinical presentation is widely variable, with most patients having mild or no symptoms, but others developing a malign disease with multi-organ failure and even death. Accumulating data from different populations have shown that obesity is a risk factor for a severe evolution of the disease, however, the mechanisms that explain this association are not clearly understood. An ominous evolution of COVID-19 has been attributed to an exacerbated inflammatory response, designed as "cytokine storm" with augmented production of cytokines/chemokines through the activation of toll-like receptors (TLR) by pathogen-associated molecular patterns, that triggers an inflammatory downstream response, mediated in part by the adaptor molecule, myeloid differentiation factor 88 (MyD88). Previous studies have reported an increased expression of MyD88 and TLRs in people with obesity, mainly in those with metabolic complications. Therefore, we hypothesize, that an underlying increased Myd88/TLR signaling may predispose to patients with obesity to develop an exaggerated and dangerous inflammatory reaction against SARS CoV-2 infection, explaining at least in part, the higher severity of COVID-19. In addition, MyD88/TLR signaling in people with obesity could have a role in the development of several chronic diseases.

Asunto(s)

COVID-19 , Factor 88 de Diferenciación Mieloide/metabolismo , Obesidad , Receptores Toll-Like/metabolismo , COVID-19/complicaciones , COVID-19/inmunología , COVID-19/fisiopatología , Síndrome de Liberación de Citoquinas/inmunología , Humanos , Obesidad/complicaciones , Obesidad/inmunología , Obesidad/fisiopatología , Pandemias , Factores de Riesgo , SARS-CoV-2 , Transducción de Señal/inmunología