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The concept of inflammation encompasses beneficial and detrimental aspects, which are referred to as infectious and sterile inflammations, respectively. Infectious inflammation plays a crucial role in host defense, whereas sterile inflammation encompasses allergic, autoimmune, and lifestyle-related diseases, leading to detrimental effects. Dendritic cells and macrophages, both of which are representative mononuclear phagocytes (MNPs), are essential for initiating immune responses, suggesting that the regulation of MNPs limits excessive inflammation. In this context, dietary components with immunomodulatory properties have been identified. Among them, soybean-derived compounds, including isoflavones, saponins, flavonoids, and bioactive peptides, act directly on MNPs to fine-tune immune responses. Notably, some soybean-derived compounds have demonstrated the ability to alleviate the symptom of allergy and autoimmunity in mouse models. In this review, we introduce and summarize the roles of soybean-derived compounds on MNP-mediated inflammatory responses. Understanding the mechanism by which soybean-derived molecules regulate MNPs could provide valuable insights for designing safe immunomodulators.
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Sepsis is a systemic inflammatory disease caused by a bacterial infection that leads to severe mortality, especially in elderly patients, because of an excessive immune response and impaired regulatory functions. Antibiotic treatment is widely accepted as the first-line therapy for sepsis; however, its excessive use has led to the emergence of multidrug-resistant bacteria in patients with sepsis. Therefore, immunotherapy may be effective in treating sepsis. Although CD8+ regulatory T cells (Tregs) are known to have immunomodulatory effects in various inflammatory diseases, their role during sepsis remains unclear. In this study, we investigated the role of CD8+ Tregs in an LPS-induced endotoxic shock model in young (8-12 wk old) and aged (18-20 mo old) mice. The adoptive transfer of CD8+ Tregs into LPS-treated young mice improved the survival rate of LPS-induced endotoxic shock. Moreover, the number of CD8+ Tregs in LPS-treated young mice increased through the induction of IL-15 produced by CD11c+ cells. In contrast, LPS-treated aged mice showed a reduced induction of CD8+ Tregs owing to the limited production of IL-15. Furthermore, CD8+ Tregs induced by treatment with the rIL-15/IL-15Rα complex prevented LPS-induced body wight loss and tissue injury in aged mice. In this study, to our knowledge, the induction of CD8+ Tregs as novel immunotherapy or adjuvant therapy for endotoxic shock might reduce the uncontrolled immune response and ultimately improve the outcomes of endotoxic shock.
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Sepsis , Choque Séptico , Ratones , Animales , Choque Séptico/terapia , Lipopolisacáridos , Linfocitos T Reguladores , Interleucina-15 , Linfocitos T CD8-positivosRESUMEN
BACKGROUND AND PURPOSE: High salt (HS) intake has been associated with hypertension and cognitive impairment. It is well known that the angiotensin II (Ang II)-AT1 receptor and prostaglandin E2 (PGE2)-EP1 receptor systems are involved in hypertension and neurotoxicity. However, the involvement of these systems in HS-mediated hypertension and emotional and cognitive impairments remains unclear. EXPERIMENTAL APPROACH: Mice were loaded with HS solution (2% NaCl drinking water) for 12 weeks, and blood pressure was monitored. Subsequently, effects of HS intake on emotional and cognitive function and tau phosphorylation in the prefrontal cortex (PFC) and hippocampus (HIP) were investigated. The involvement of Ang II-AT1 and PGE2-EP1 systems in HS-induced hypertension and neuronal and behavioural impairments was examined by treatment with losartan, an AT1 receptor blocker (ARB), or EP1 gene knockout. KEY RESULTS: We demonstrate that hypertension and impaired social behaviour and object recognition memory following HS intake may be associated with tau hyperphosphorylation, decreased phosphorylation of Ca2+ /calmodulin-dependent protein kinase II (CaMKII), and postsynaptic density protein 95 (PSD95) expression in the PFC and HIP of mice. These changes were blocked by pharmacological treatment with losartan or EP1 receptor gene knockout. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that the interaction of Ang II-AT1 receptor and PGE2-EP1 receptor systems could be novel therapeutic targets for hypertension-induced cognitive impairment.
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Disfunción Cognitiva , Hipertensión , Ratones , Animales , Losartán/farmacología , Cloruro de Sodio , Dinoprostona/metabolismo , Angiotensina II/farmacología , Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina , Hipertensión/metabolismo , Cloruro de Sodio Dietético , Receptor de Angiotensina Tipo 1/metabolismoRESUMEN
It is considered that sensory neurons extend into the tumor microenvironment (TME), which could be associated with tumor growth. However, little is known about how sensory signaling could promote tumor progression. In this study, chemogenetic activation of transient receptor potential vanilloid 1 (Trpv1)-positive sensory neurons (C-fibers) by the microinjection of AAV-hSyn-FLEX-hM3Dq-mCherry into the sciatic nerve dramatically increased tumor volume in tumor-bearing Trpv1-Cre mice. This activation in Trpv1::hM3Dq mice that had undergone tumor transplantation significantly reduced the population of tumor-infiltrating CD4+ T cells and increased the mRNA level of the M2-macrophage marker, CX3C motif chemokine receptor 1 (Cx3cr1) in immunosuppressive cells, such as tumor-associated macrophages (TAMs) and tumor-infiltrating monocytic myeloid-derived suppressor cells (M-MDSCs). Under these conditions, we found a significant correlation between the decreased expression of the M1-macrophage marker Tnf and tumor volume. These findings suggest that repeated activation of Trpv1-positive sensory neurons may facilitate tumor growth along with changes in tumor-infiltrating immune cells.
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Antineoplásicos , Ratones , Animales , Antineoplásicos/metabolismo , Macrófagos/metabolismo , Células Receptoras Sensoriales/metabolismo , Línea Celular Tumoral , Trasplante de Neoplasias , Microambiente Tumoral , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismoRESUMEN
A growing body of evidence suggests that excess stress could aggravate tumor progression. The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the adaptation to stress because the hypothalamic-pituitary-adrenal (HPA) axis can be activated by inducing the release of corticotropin-releasing hormone (CRH) from the PVN. In this study, we used pharmacogenetic techniques to investigate whether concomitant activation of CRHPVN neurons could directly contribute to tumor progression. Tumor growth was significantly promoted by repeated activation of CRHPVN neurons, which was followed by an increase in the plasma levels of corticosterone. Consistent with these results, chronic administration of glucocorticoids induced tumor progression. Under the concomitant activation of CRHPVN neurons, the number of cytotoxic CD8+ T cells in the tumor microenvironment was dramatically decreased, and the mRNA expression levels of hypoxia inducible factor 1 subunit α (HIF1α), glucocorticoid receptor (GR) and Tsc22d3 were upregulated in inhibitory lymphocytes, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Furthermore, the mRNA levels of various kinds of driver molecules related to tumor progression and tumor metastasis were prominently elevated in cancer cells by concomitant activation of CRHPVN neurons. These findings suggest that repeated activation of the PVN-CRHergic system may aggravate tumor growth through a central-peripheral-associated tumor immune system.
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Linfocitos T CD8-positivos , Núcleo Hipotalámico Paraventricular , Núcleo Hipotalámico Paraventricular/metabolismo , Linfocitos T CD8-positivos/metabolismo , Hipotálamo/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Corticosterona , Neuronas/metabolismo , ARN Mensajero/metabolismoRESUMEN
The partial loss of liver due to liver transplantation or acute liver failure induces rapid liver regeneration. Recently, we reported that the selective inhibition of indoleamine 2,3dioxygenase (Ido) 1 promotes early liver regeneration. However, the role of Ido2 in liver regeneration remains unclear. Wildtype (WT) and Ido2deficient (Ido2KO) mice were subjected to 70% partial hepatectomy (PHx). Hepatocyte growth was measured using immunostaining. The mRNA expression of inflammatory cytokines and production of kynurenine in intrahepatic mononuclear cells (MNCs) were analyzed using reverse transcriptionquantitative PCR and highperformance liquid chromatography. The activation of NFκB was determined by both immunocytochemistry and western blotting analysis. The ratio of liver to body weight and the frequency of proliferation cells after PHx were significantly higher in Ido2KO mice compared with in WT mice. The expression of IL6 and TNFα in MNCs were transiently increased in Ido2KO mice. The nuclear transport of NFκB was significantly higher in peritoneal macrophages of Ido2KO mice compared with WT mice. These results suggested that Ido2 deficiency resulted in transiently increased production of inflammatory cytokines through the activation of NFkB, thereby promoting liver regeneration. Therefore, the regulation of Ido2 expression in MNCs may play a therapeutic role in liver regeneration under injury and disease conditions.
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Indolamina-Pirrol 2,3,-Dioxigenasa , Regeneración Hepática , Ratones , Animales , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , FN-kappa B , Peso CorporalRESUMEN
BACKGROUND: It has been considered that activation of peripheral µ-opioid receptors (MORs) induces side effects of opioids. In this study, we investigated the possible improvement of the immune system in tumour-bearing mice by systemic administration of the peripheral MOR antagonist naldemedine. METHODS: The inhibitory effect of naldemedine on MOR-mediated signalling was tested by cAMP inhibition and ß-arrestin recruitment assays using cultured cells. We assessed possible changes in tumour progression and the number of splenic lymphocytes in tumour-bearing mice under the repeated oral administration of naldemedine. RESULTS: Treatment with naldemedine produced a dose-dependent inhibition of both the decrease in the cAMP level and the increase in ß-arrestin recruitment induced by the MOR agonists. Repeated treatment with naldemedine at a dose that reversed the morphine-induced inhibition of gastrointestinal transport, but not antinociception, significantly decreased tumour volume and prolonged survival in tumour-transplanted mice. Naldemedine administration significantly decreased the increased expression of immune checkpoint-related genes and recovered the decreased level of toll-like receptor 4 in splenic lymphocytes in tumour-bearing mice. CONCLUSIONS: The blockade of peripheral MOR may induce an anti-tumour effect through the recovery of T-cell exhaustion and promotion of the tumour-killing system.
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Neoplasias , Receptores Opioides mu , Analgésicos Opioides/efectos adversos , Animales , Sistema Inmunológico/metabolismo , Ratones , Derivados de la Morfina , Naltrexona/análogos & derivados , Neoplasias/inducido químicamente , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Receptor Toll-Like 4/metabolismo , beta-Arrestinas/metabolismoRESUMEN
Various cancer cells require massive amounts of glucose as an energy source for their dysregulated growth. Although Dallose, a rare sugar, inhibits tumor cell growth via inhibition of glucose uptake, a few cells can survive after treatment. However, the mechanism by which Dalloseresistant cells are generated remains unclear. Here, we investigated the properties of Dalloseresistant cells and evaluated the efficacy of combined treatment with this rare sugar and antitumor drugs. To this end, we established a Dalloseresistant tumor cell line and prepared a C57BL/6J mouse tumor xenograft model using Lewis lung carcinoma (LLC) cells. Xenograftbearing mice were treated with Dallose (9 g/kg) and/or hydroxychloroquine (HCQ, 60 mg/kg), an autophagy inhibitor, for two weeks. Although Dallose inhibited LLC cell growth in a dosedependent manner, a few cells survived. The upregulation of LC3II, a classical autophagy marker, and the downregulation of mTOR and its downstream molecule Beclin1 were observed in established Dalloseresistant LLC cells, which were more sensitive to cell death induced by HCQ. Similarly, in the tumor xenograft model, the tumor volume in mice cotreated with Dallose and HCQ was considerably smaller than that in untreated or HCQtreated mice. Importantly, the administration of Dallose induced autophagy selectively at the tumor site of the xenograftbearing mice. These results provide a new therapeutic strategy targeting autophagy which is induced in tumor cells by Dallose administration, and may be used to improve therapies for lung cancer.
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Carcinoma Pulmonar de Lewis , Hidroxicloroquina , Animales , Autofagia , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Carcinoma Pulmonar de Lewis/metabolismo , Línea Celular Tumoral , Glucosa , Humanos , Hidroxicloroquina/farmacología , Hidroxicloroquina/uso terapéutico , Ratones , Ratones Endogámicos C57BLRESUMEN
Recent research has suggested that the mesolimbic dopamine network that mainly terminates in the nucleus accumbens may positively control the peripheral immune system. The activation of dopamine receptors in neurons in the nucleus accumbens by the release of endogenous dopamine is thus expected to contribute to efferent immune regulation. As in the stimulation of Gs-coupled dopamine D1-receptors or Gi-coupled D2-receptors by endogenous dopamine, we investigated whether specific stimulation of dopamine D1-receptor-expressing neurons or inhibition of dopamine D2-receptor-expressing neurons in the nucleus accumbens could produce anti-tumor effects and improve the immune system in transgenic mice using pharmacogenetic techniques. Repeated stimulation of D1-receptor-expressing neurons in either the medial shell, lateral shell or core regions of the nucleus accumbens significantly decreased tumor volume under a state of tumor transplantation, whereas repeated suppression of D2-receptor-expressing neurons in these areas had no effect on this event. The number of splenic CD8+ T cells was significantly increased following repeated stimulation of D1-receptor-expressing neurons in the nucleus accumbens of mice with tumor transplantation. Furthermore, this stimulation produced a significant reduction in the population of splenic CD8+ T cells that expressed immune checkpoint-related inhibitory receptors, PD-1, TIM-3 and LAG-3. These findings suggest that repeated stimulation of D1-receptor-expressing neurons (probably D1-receptor-expressing medium spiny neurons) in the nucleus accumbens suppressed tumor progression and improved the immune system by suppressing the exhaustion of splenic CD8+ T cells.
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Dopamina , Núcleo Accumbens , Animales , Linfocitos T CD8-positivos , Ratones , Ratones Transgénicos , NeuronasRESUMEN
Fukuyama congenital muscular dystrophy (FCMD) is a severe, intractable genetic disease that affects the skeletal muscle, eyes, and brain and is attributed to a defect in alpha dystroglycan (αDG) O-mannosyl glycosylation. We previously established disease models of FCMD; however, they did not fully recapitulate the phenotypes observed in human patients. In this study, we generated induced pluripotent stem cells (iPSCs) from a human FCMD patient and differentiated these cells into three-dimensional brain organoids and skeletal muscle. The brain organoids successfully mimicked patient phenotypes not reliably reproduced by existing models, including decreased αDG glycosylation and abnormal radial glial (RG) fiber migration. The basic polycyclic compound Mannan-007 (Mn007) restored αDG glycosylation in the brain and muscle models tested and partially rescued the abnormal RG fiber migration observed in cortical organoids. Therefore, our study underscores the importance of αDG O-mannosyl glycans for normal RG fiber architecture and proper neuronal migration in corticogenesis.
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Despite advances in our understanding of endotoxic shock, novel therapeutic interventions that can reduce the burden of sepsis remain elusive. Current treatment options are limited, and it is only through refinements in the ways that we deliver supportive care that mortality has fallen over the years. In this study, the role of kynurenine 3-monooxygenase (KMO) in immune regulation was examined in LPS-induced endotoxemia using KMO-/- and KMO+/+ mice treated with the KMO inhibitor Ro61-8048. We showed that LPS-induced or cecal ligation and puncture-induced mortality and hepatic IL-6 production increased in the absence of KMO, possibly involving increased activating transcription factor 4 (ATF4) signaling in hepatic macrophages. Moreover, treatment of septic mice with 3-hydroxykynurenine reduced mortality rates and inflammatory responses regardless of the presence or absence of KMO. According to our results, the administration of 3-hydroxykynurenine as part of the treatment approach for sepsis or as an adjuvant therapy might reduce the overproduction of IL-6, which is responsible for severe endotoxemia, and ultimately improve the survival rates of patients with sepsis.
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Interleucina-6/metabolismo , Quinurenina 3-Monooxigenasa/metabolismo , Quinurenina/análogos & derivados , Choque Séptico/tratamiento farmacológico , Factor de Transcripción Activador 4/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Quinurenina/metabolismo , Quinurenina/uso terapéutico , Quinurenina 3-Monooxigenasa/antagonistas & inhibidores , Quinurenina 3-Monooxigenasa/genética , Lipopolisacáridos/inmunología , Hígado/citología , Hígado/inmunología , Hígado/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Noqueados , Choque Séptico/inmunología , Choque Séptico/patología , Transducción de Señal/genética , Sulfonamidas/farmacología , Tiazoles/farmacologíaRESUMEN
In the present study, we demonstrated that there is a direct relationship between scratching behaviors induced by itch and functional changes in the brain reward system. Using a conditional place preference test, the rewarding effect was clearly evoked by scratching under both acute and chronic itch stimuli. The induction of ΔFosB, a member of the Fos family of transcription factors, was observed in dopamine transporter (DAT)-positive dopamine neurons in the ventral tegmental area (VTA) of mice suffering from a chronic itch sensation. Based on a cellular analysis of scratching-activated neurons, these neurons highly expressed tyrosine hydroxylase (TH) and DAT genes in the VTA. Furthermore, in an in vivo microdialysis study, the levels of extracellular dopamine in the nucleus accumbens (NAcc) were significantly increased by transient scratching behaviors. To specifically suppress the mesolimbic dopaminergic pathway using pharmacogenetics, we used the TH-cre/hM4Di mice. Pharmacogenetic suppression of mesolimbic dopaminergic neurons significantly decreased scratching behaviors. Under the itch condition with scratching behaviors restricted by an Elizabethan collar, the induction of ΔFosB was found mostly in corticotropin-releasing hormone (CRH)-containing neurons of the hypothalamic paraventricular nucleus (PVN). These findings suggest that repetitive abnormal scratching behaviors under acute and chronic itch stimuli may activate mesolimbic dopamine neurons along with pleasant emotions, while the restriction of such scratching behaviors may initially induce the activation of PVN-CRH neurons associated with stress.
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Prurito/fisiopatología , Prurito/psicología , Recompensa , Área Tegmental Ventral/fisiopatología , Enfermedad Aguda , Animales , Conducta Animal/fisiología , Enfermedad Crónica , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Neuronas Dopaminérgicas/metabolismo , Expresión Génica , Histamina/administración & dosificación , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Núcleo Accumbens/fisiopatología , Pruebas de Farmacogenómica , Cloruro de Picrilo/administración & dosificación , Prurito/genética , Tirosina 3-Monooxigenasa/genéticaRESUMEN
BACKGROUND: Inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, is characterized by chronic intestinal inflammation leading to intestinal mucosal damage. Inflammatory bowel disease causes dysregulation of mucosal T cell responses, especially the responses of CD4+ T cells. Previously, we demonstrated that indoleamine-2,3-dioxygenase plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfate (TNBS)-induced colitis. Although indoleamine-2,3-dioxygenase exerts immunosuppressive effects by altering the local concentration of tryptophan (Trp) and immunomodulatory Trp metabolites, the specific changes in immune regulation during colitis caused by Trp metabolites and its related enzymes remain unclear. AIM: To investigate role of kynurenine 3-monooxygenase (KMO) in TNBS-induced colitis and involvement of Trp metabolites in maintenance of intestinal homeostasis. METHODS: Colitis was induced in eight-week-old male KMO+/+ or KMO-/- mice of C57BL/6N background using TNBS. Three days later, the colon was used for hematoxylin-eosin staining for histological grading, immunohistochemical or immunofluorescence staining for KMO, cytokines, and immune cells. Inflammatory and anti-inflammatory cytokines were measured using quantitative RT-PCR, and kynurenine (Kyn) pathway metabolites were measured by high-performance liquid chromatography. The cell proportions of colonic lamina propria and mesenteric lymph nodes were analyzed by flow cytometry. RESULTS: KMO expression levels in the colonic mononuclear phagocytes, including dendritic cells and macrophages increased upon TNBS induction. Notably, KMO deficiency reduced TNBS-induced colitis, resulting in an increased frequency of Foxp3+ regulatory T cells and increased mRNA and protein levels of anti-inflammatory cytokines, including transforming growth factor-ß and interleukin-10. CONCLUSION: Absence of KMO reduced TNBS-induced colitis via generation of Foxp3+ regulatory T cells by producing Kyn. Thus, Kyn may play a therapeutic role in colon protection during colitis.
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Colitis/tratamiento farmacológico , Colitis/inmunología , Inmunosupresores/uso terapéutico , Quinurenina/uso terapéutico , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Colitis/inducido químicamente , Colon/efectos de los fármacos , Modelos Animales de Enfermedad , Homeostasis , Masculino , Ratones , Ratones Endogámicos C57BL , Sulfatos , Trinitrobencenos , Triptófano/metabolismoRESUMEN
Propolis possesses several immunological functions. We recently generated a conditional Ca2+ biosensor yellow cameleon (YC3.60) transgenic mouse line and established a five-dimensional (5D) (x, y, z, time, and Ca2+ signaling) system for intravital imaging of lymphoid tissues, including Peyer's patches (PPs). To assess the effects of propolis on immune cells, we analyzed Ca2+ signaling in vitro and in vivo using CD11c-Cre/YC3.60flox transgenic mice, in which CD11c+ dendritic cells (DCs) specifically express YC3.60. We found that propolis induced Ca2+ signaling in DCs in the PPs. Intravital imaging of PPs also showed that an intraperitoneal injection of propolis augmented Ca2+ signaling in CD11c+ cells, suggesting that propolis possesses immune-stimulating activity. Furthermore, CD11c+ cells in PPs in mice administrated propolis indicated an increase in Ca2+ signaling. Our results indicate that propolis induces immunogenicity under physiological conditions.
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The intestinal mucosa is a physiological barrier for most microbes, including both commensal bacteria and invading pathogens. Under homeostatic conditions, immunoglobulin A (IgA) is the major immunoglobulin isotype in the intestinal mucosa. Microbes stimulate the production of IgA, which controls bacterial translocation and neutralizes bacterial toxins at the intestinal mucosal surface. In the intestinal mucosa, dendritic cells (DCs), specialized antigen-presenting cells, regulate both T-cell-dependent (TD) and -independent (TI) immune responses. The intestinal DCs are a heterogeneous population that includes unique subsets that induce IgA synthesis in B cells. The characteristics of intestinal DCs are strongly influenced by the microenvironment, including the presence of commensal bacterial metabolites and epithelial cell-derived soluble factors. In this review, we summarize the ontogeny, classification, and function of intestinal DCs and how the intestinal microenvironment conditions DCs and their precursors to become the mucosal phenotype, in particular to regulate IgA production, after they arrive at the intestine. Understanding the mechanism of IgA synthesis could provide insights for designing effective mucosal vaccines.
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Células Dendríticas/inmunología , Inmunoglobulina A/biosíntesis , Mucosa Intestinal/inmunología , Animales , Microambiente Celular , Humanos , Mucosa Intestinal/citologíaRESUMEN
Interleukin 27 (IL-27) has been identified as a potent cytokine in the differentiation of type 1 regulatory T (Tr1) cells through interactions with several key elements, including transcription factors such as aryl hydrocarbon receptor and IL-21. Autocrine production of IL-21 is known to be important for maintaining IL-10 expression by Tr1 cells. Although previous studies have shown that the phosphoinositide 3-kinase (PI3K) -Akt axis contributes to the differentiation of helper T-cell subsets, the role of the PI3K pathway on Tr1 cell differentiation remains to be elucidated. Here, we demonstrate that suppression of the PI3K-Akt pathway results in impairment of IL-27-induced Tr1 (IL-27-Tr1) cell differentiation in vitro and in vivo. Furthermore, this suppression down-regulates IL-21 receptor expression by Tr1 cells, followed by suppression of IL-10 expression by IL-27-Tr1 cells. These results suggest that the PI3K pathway enhances IL-10 expression by IL-27-Tr1 cells through up-regulation of IL-21 receptors.
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Diferenciación Celular/efectos de los fármacos , Interleucina-27/farmacología , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Animales , Células Cultivadas , Femenino , Proteína Forkhead Box O1/inmunología , Proteína Forkhead Box O1/metabolismo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Genotipo , Interleucina-10/genética , Interleucina-10/metabolismo , Subunidad alfa del Receptor de Interleucina-21/inmunología , Subunidad alfa del Receptor de Interleucina-21/metabolismo , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Fenotipo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/genética , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
Hemophagocytic syndrome (HPS) is frequently associated with hematopoietic stem cell transplantation and is treated with some benefit derived from TNF-α inhibitors. However, the mechanisms of how HPS occurs and how a TNF-α inhibitor exerts some benefit to HPS management have remained unclear. We evaluated the effect of toll-like receptor (TLR) ligands, especially focusing on cytosine-phosphorothionate-guanine oligodeoxynucleotide (CpG), a TLR9 ligand, on HPS in mice that underwent transplantation with syngeneic or allogeneic bone marrow (BM) cells (Syn-BMT, Allo-BMT), or with allogeneic BM cells plus splenocytes to promote graft-versus-host disease (GVHD mice). Hemophagocytosis was a common feature early after all BMT, but it subsided in Syn-BMT and Allo-BMT mice. In GVHD mice, however, hemophagocytosis persisted and was accompanied by upregulated production of IFN-γ but not TNF-α, and it was suppressed by blockade of IFN-γ but not TNF-α. A single injection of the TLR9 ligand CpG promoted HPS in all BMT mice and was lethal in GVHD mice, accompanied by greatly upregulated production of TNF-α, IL-6, and IFN-γ. Blocking of TNF-α, but not IL-6 or IFN-γ, suppressed CpG-induced HPS in all BMT mice and rescued GVHD mice from CpG-induced mortality. Thus, TLR9 signaling mediates TNF-α-driven HPS in BMT mice and is effectively treated through TNF-α inhibition.
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Trasplante de Médula Ósea/métodos , Linfohistiocitosis Hemofagocítica/inmunología , Oligodesoxirribonucleótidos/farmacología , Receptor Toll-Like 9/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Animales , Anticuerpos Monoclonales/farmacología , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Trasplante de Médula Ósea/efectos adversos , Islas de CpG/inmunología , Etanercept/farmacología , Rayos gamma , Regulación de la Expresión Génica , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Interferón gamma/antagonistas & inhibidores , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Linfocitos/citología , Linfocitos/inmunología , Linfohistiocitosis Hemofagocítica/etiología , Linfohistiocitosis Hemofagocítica/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Oligodesoxirribonucleótidos/antagonistas & inhibidores , Transducción de Señal , Receptor Toll-Like 9/genética , Trasplante Homólogo , Trasplante Isogénico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genética , Irradiación Corporal TotalRESUMEN
Inflammation is an immune response against both internal and external antigens in organisms, particularly in mammals, and includes both uncontrolled chronic and low-grade inflammations. Uncontrolled chronic inflammation often leads to severe diseases such as vascular disease, arthritis, cancer, diabete, allergy, and autoimmunity. On the other hand, low-grade inflammation is recognized as a relationship between obesity and risk of metabolic syndrome. Elevated production of pro-inflammatory cytokines and mediators is commonly observed in patients with uncontrolled or low-grade inflammation-associated diseases. Plants have been generated phytochemicals to overcome inflammations and infections through evolution. Phytochemicals belong to alkaloids, polyphenols, flavonoids, coumarins, and terpenoids. The consumption of soybeans plays a role in immune modulation through their components such as isoflavones, saponins, and anthocyanins. Recently, it was reported that the application of phytochemicals into patients with inflammatory diseases improves their symptoms. Therefore, it is important to identify novel phytochemicals with immunomodulatory activities. This review introduces and discusses recent advances and patents regarding soybean or processed soy food compounds which exhibit immunomodulatory activity in immune diseases, particularly allergy, by mediating the suppression of inflammatory pathways.
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Glycine max/química , Hipersensibilidad/prevención & control , Factores Inmunológicos/uso terapéutico , Inflamación/tratamiento farmacológico , Patentes como Asunto , Fitoquímicos/uso terapéutico , Alimentos de Soja , Animales , Manipulación de Alimentos , Humanos , Hipersensibilidad/patología , Factores Inmunológicos/farmacología , Isoflavonas/farmacología , Isoflavonas/uso terapéutico , Fitoquímicos/farmacología , Saponinas/farmacología , Saponinas/uso terapéuticoRESUMEN
RATIONALE: Patients who developed acute respiratory distress syndrome (ARDS) after infection with severe respiratory viruses (e.g., severe acute respiratory syndrome-coronavirus, H5N1 avian influenza virus), exhibited unusually high levels of CXCL10, which belongs to the non-ELR (glutamic-leucine-arginine) CXC chemokine superfamily. CXCL10 may not be a bystander to the severe virus infection but may directly contribute to the pathogenesis of neutrophil-mediated, excessive pulmonary inflammation. OBJECTIVES: We investigated the contribution of CXCL10 and its receptor CXCR3 axis to the pathogenesis of ARDS with nonviral and viral origins. METHODS: We induced nonviral ARDS by acid aspiration and viral ARDS by intratracheal influenza virus infection in wild-type mice and mice deficient in CXCL10, CXCR3, IFNAR1 (IFN-α/ß receptor 1), or TIR domain-containing adaptor inducing IFN-ß (TRIF). MEASUREMENTS AND MAIN RESULTS: We found that the mice lacking CXCL10 or CXCR3 demonstrated improved severity and survival of nonviral and viral ARDS, whereas mice that lack IFNAR1 did not control the severity of ARDS in vivo. The increased levels of CXCL10 in lungs with ARDS originate to a large extent from infiltrated pulmonary neutrophils, which express a unique CXCR3 receptor via TRIF. CXCL10-CXCR3 acts in an autocrine fashion on the oxidative burst and chemotaxis in the inflamed neutrophils, leading to fulminant pulmonary inflammation. CONCLUSIONS: CXCL10-CXCR3 signaling appears to be a critical factor for the exacerbation of the pathology of ARDS. Thus, the CXCL10-CXCR3 axis could represent a prime therapeutic target in the treatment of the acute phase of ARDS of nonviral and viral origins.
Asunto(s)
Quimiocina CXCL10/fisiología , Lesión Pulmonar/fisiopatología , Neutrófilos/fisiología , Infecciones por Orthomyxoviridae/fisiopatología , Receptores CXCR3/fisiología , Síndrome de Dificultad Respiratoria/fisiopatología , Anciano , Anciano de 80 o más Años , Animales , Quimiocina CXCL10/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Subtipo H5N1 del Virus de la Influenza A , Lesión Pulmonar/inmunología , Lesión Pulmonar/virología , Masculino , Ratones , Ratones Endogámicos , Persona de Mediana Edad , Neutrófilos/inmunología , Infecciones por Orthomyxoviridae/inmunología , Análisis por Matrices de Proteínas , Ratas , Ratas Sprague-Dawley , Receptores CXCR3/efectos de los fármacos , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/virologíaRESUMEN
Although both conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs) are present in the gut-associated lymphoid tissues (GALT), the roles of pDCs in the gut remain largely unknown. Here we show a critical role for pDCs in T cell-independent (TI) IgA production by B cells in the GALT. When pDCs of the mesenteric lymph nodes (MLNs) and Peyer's patches (PPs) (which are representative GALT) were cultured with naive B cells to induce TI IgA class switch recombination (CSR), IgA production was substantially higher than in cocultures of these cells with cDCs. IgA production was dependent on APRIL and BAFF production by pDCs. Importantly, pDC expression of APRIL and BAFF was dependent on stromal cell-derived type I IFN signaling under steady-state conditions. Our findings provide insight into the molecular basis of pDC conditioning to induce mucosal TI IgA production, which may lead to improvements in vaccination strategies and treatment for mucosal-related disorders.