RESUMEN
Malassezia, the most abundant fungal commensal on the mammalian skin, has been linked to several inflammatory skin diseases such as atopic dermatitis, seborrheic dermatitis and psoriasis. This study reveals that epicutaneous application with Malassezia globosa (M. globosa) triggers skin inflammation in mice. RNA-sequencing of the resulting mouse lesions indicates activation of Interleukin-17 (IL-17) signaling and T helper 17 (Th17) cells differentiation pathways by M. globosa. Furthermore, our findings demonstrate a significant upregulation of IL-23, IL-23R, IL-17A, and IL-22 expressions, along with an increase in the proportion of Th17 and pathogenic Th17 cells in mouse skin exposed to M. globosa. In vitro experiments illustrate that M. globosa prompts human primary keratinocytes to secrete IL-23 via TLR2/MyD88/NF-κB signaling. This IL-23 secretion by keratinocytes is shown to be adequate for inducing the differentiation of pathogenic Th17 cells in the skin. Overall, these results underscore the significant role of Malassezia in exacerbating skin inflammation by stimulating IL-23 secretion by keratinocytes and promoting the differentiation of pathogenic Th17 cells.
Asunto(s)
Diferenciación Celular , Interleucina-23 , Queratinocitos , Malassezia , Células Th17 , Malassezia/inmunología , Queratinocitos/microbiología , Queratinocitos/inmunología , Queratinocitos/metabolismo , Células Th17/inmunología , Animales , Interleucina-23/metabolismo , Humanos , Ratones , Transducción de Señal , FN-kappa B/metabolismo , Receptor Toll-Like 2/metabolismo , Interleucina-17/metabolismo , Piel/microbiología , Piel/patología , Piel/inmunología , Modelos Animales de Enfermedad , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Células Cultivadas , Ratones Endogámicos C57BL , Interleucina-22RESUMEN
The innate immune response is triggered rapidly after injury and its spatiotemporal dynamics are critical for regeneration; however, many questions remain about its exact role. Here we show that MyD88, a key component of the innate immune response, controls not only the inflammatory but also the fibrotic response during zebrafish cardiac regeneration. We find in cryoinjured myd88-/- ventricles a significant reduction in neutrophil and macrophage numbers and the expansion of a collagen-rich endocardial population. Further analyses reveal compromised PI3K/AKT pathway activation in the myd88-/- endocardium and increased myofibroblasts and scarring. Notably, endothelial-specific overexpression of myd88 reverses these neutrophil, fibrotic and scarring phenotypes. Mechanistically, we identify the endocardial-derived chemokine gene cxcl18b as a target of the MyD88 signaling pathway, and using loss-of-function and gain-of-function tools, we show that it controls neutrophil recruitment. Altogether, these findings shed light on the pivotal role of MyD88 in modulating inflammation and fibrosis during tissue regeneration.
Asunto(s)
Fibrosis , Inmunidad Innata , Factor 88 de Diferenciación Mieloide , Regeneración , Transducción de Señal , Proteínas de Pez Cebra , Pez Cebra , Animales , Animales Modificados Genéticamente , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Endocardio/metabolismo , Endocardio/patología , Endocardio/inmunología , Corazón/fisiopatología , Inmunidad Innata/genética , Macrófagos/metabolismo , Macrófagos/inmunología , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/patología , Infiltración Neutrófila , Neutrófilos/metabolismo , Neutrófilos/inmunología , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Regeneración/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
The excessive inflammation caused by the prolonged activation of Toll-like receptor 4 (TLR4) and its downstream signaling pathways leads to sepsis. CD14-mediated endocytosis of TLR4 is the key step to control the amount of TLR4 on cell membrane and the activity of downstream pathways. The actin cytoskeleton is necessary for receptor-mediated endocytosis, but its role in TLR4 endocytosis remains elusive. Here we show that Tropomodulin 1 (Tmod1), an actin capping protein, inhibited lipopolysaccharide (LPS)-induced TLR4 endocytosis and intracellular trafficking in macrophages. Thus it resulted in increased surface TLR4 and the upregulation of myeloid differentiation factor 88 (MyD88)-dependent pathway and the downregulation of TIR domain-containing adaptor-inducing interferon-ß (TRIF)-dependent pathway, leading to the enhanced secretion of inflammatory cytokines, such as TNF-α and IL-6, and the reduced secretion of cytokines, such as IFN-ß. Macrophages deficient with Tmod1 relieved the inflammatory response in LPS-induced acute lung injury mouse model. Mechanistically, Tmod1 negatively regulated LPS-induced TLR4 endocytosis and inflammatory response through modulating the activity of CD14/Syk/PLCγ2/IP3/Ca2+ signaling pathway, the reorganization of actin cytoskeleton, and the membrane tension. Therefore, Tmod1 is a key regulator of inflammatory response and immune functions in macrophages and may be a potential target for the treatment of excessive inflammation and sepsis.
Asunto(s)
Endocitosis , Inflamación , Lipopolisacáridos , Macrófagos , Ratones Endogámicos C57BL , Transducción de Señal , Receptor Toll-Like 4 , Tropomodulina , Animales , Receptor Toll-Like 4/metabolismo , Lipopolisacáridos/farmacología , Ratones , Macrófagos/metabolismo , Macrófagos/inmunología , Inflamación/metabolismo , Inflamación/patología , Tropomodulina/metabolismo , Tropomodulina/genética , Citocinas/metabolismo , Células RAW 264.7 , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Receptores de Lipopolisacáridos/metabolismo , Masculino , Ratones Noqueados , Citoesqueleto de Actina/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/patologíaRESUMEN
Waldenström macroglobulinemia (WM) is a B-cell lymphoma characterized by the presence of bone marrow lymphoplasmacytic infiltration and circulating monoclonal immunoglobulin M protein. The clinical presentation of WM is variable, ranging from gradually progressive cytopenias, organomegaly, fatigue, B symptoms, and peripheral neuropathy to the more emergent presentation with symptomatic hyperviscosity, cryoglobulinemia, hemolytic anemia-associated symptoms, acquired von Willebrand disease or acquired hemophilia-associated bleeding. Approximately 1 in 5 patients with WM are asymptomatic at diagnosis and classified as having smoldering WM, not requiring WM-directed therapy. Although WM typically has an indolent, relapsing-remitting course, the outcomes are heterogeneous. The prognosis of patients with WM is known to be impacted by certain clinical and laboratory features at initial presentation, with advanced age, elevated serum lactate dehydrogenase, and low serum albumin unfavorably affecting the outcome. Although complications such as histologic transformation or light and/or heavy chain (AL/ALH) amyloidosis are infrequent, their occurrence adversely influences the disease course. The International Prognostic Staging System for WM (IPSS-WM) is a validated model, often used in clinical practice, but needs to be reexamined in the current era. The discovery of the recurrent MYD88L265P gain-of-function point mutation and the subclonal CXCR4 mutations has helped improve our understanding of the WM biology, and the prognostic impact of these mutations is under evaluation, with somewhat inconsistent findings thus far across studies. This review discusses the clinical presentation, diagnostic criteria, and prognostic markers of WM.
Asunto(s)
Macroglobulinemia de Waldenström , Humanos , Macroglobulinemia de Waldenström/diagnóstico , Pronóstico , Medición de Riesgo , Factor 88 de Diferenciación Mieloide/genéticaRESUMEN
Talaromycosis, caused by Talaromyces marneffei (T. marneffei, formerly known as Penicillium marneffei), is an opportunistic invasive mycosis endemic in tropical and subtropical areas of Asia with high mortality rate. Despite various infection models established to study the immunological interaction between T. marneffei and the host, the pathogenicity of this fungus is not yet fully understood. So far, Drosophila melanogaster, a well-established genetic model organism to study innate immunity, has not been used in related research on T. marneffei. In this study, we provide the initial characterization of a systemic infection model of T. marneffei in the D. melanogaster host. Survival curves and fungal loads were tested as well as Toll pathway activation was quantified by RT-qPCR of several antimicrobial peptide (AMP) genes including Drosomycin, Metchnikowin, and Bomanin Short 1. We discovered that whereas most wild-type flies were able to overcome the infection, MyD88 or Toll mutant flies failed to prevent fungal dissemination and proliferation and ultimately succumbed to this challenge. Unexpectedly, the induction of classical Toll pathway activation readouts, Drosomycin and Bomanin Short 1, by live or killed T. marneffei was quite limited in wild-type flies, suggesting that the fungus largely escapes detection by the systemic immune system. This unusual situation of a poor systemic activation of the Toll pathway and a strong susceptibility phenotype of MyD88/Toll might be accounted for by a requirement for this host defence in only specific tissues, a hypothesis that remains to be rigorously tested.
Asunto(s)
Proteínas de Drosophila , Drosophila melanogaster , Factor 88 de Diferenciación Mieloide , Talaromyces , Receptores Toll-Like , Animales , Talaromyces/genética , Talaromyces/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Drosophila melanogaster/microbiología , Drosophila melanogaster/inmunología , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Receptores Toll-Like/metabolismo , Receptores Toll-Like/genética , Micosis/inmunología , Micosis/microbiología , Inmunidad Innata , Transducción de Señal , Antígenos de Diferenciación , Receptores Inmunológicos , Proteínas Adaptadoras Transductoras de SeñalesRESUMEN
Rabies is a fatal neurological infectious disease caused by rabies virus (RABV), which invades the central nervous system (CNS). RABV with varying virulence regulates chemokine expression, and the mechanisms of signaling pathway activation remains to be elucidated. The relationship between Toll-like receptors (TLRs) and immune response induced by RABV has not been fully clarified. Here, we investigated the role of TLR7 in the immune response induced by RABV, and one-way analysis of variance (ANOVA) was employed to evaluate the data. We found that different RABV strains (SC16, HN10, CVS-11) significantly increased CCL2, CXCL10 and IL-6 production. Blocking assays indicated that the TLR7 inhibitor reduced the expression of CCL2, CXCL10 and IL-6 (p < 0.01). The activation of the Myd88 pathway in BV-2 cells stimulated by RABV was TLR7-dependent, whereas the inhibition of Myd88 activity reduced the expression of CCL2, CXCL10 and IL-6 (p < 0.01). Meanwhile, the RABV stimulation of BV-2 cells resulted in TRL7-mediated activation of NF-κB and induced the nuclear translocation of NF-κB p65. CCL2, CXCL10 and IL-6 release was attenuated by the specific NF-κB inhibitor used (p < 0.01). The findings above demonstrate that RABV-induced expression of CCL2, CXCL10 and IL-6 involves Myd88 and NF-κB pathways via the TLR7 signal.
Asunto(s)
Factor 88 de Diferenciación Mieloide , FN-kappa B , Virus de la Rabia , Transducción de Señal , Receptor Toll-Like 7 , Receptor Toll-Like 7/metabolismo , Animales , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Virus de la Rabia/patogenicidad , Virus de la Rabia/inmunología , Ratones , FN-kappa B/metabolismo , Línea Celular , Interleucina-6/metabolismo , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/genética , Rabia/virología , Rabia/metabolismo , Rabia/inmunología , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Inflamación/metabolismoRESUMEN
BACKGROUND: Ocular adnexal B cell lymphoma is the most common orbital malignancy in adults. Large chromosomal translocations and alterations in cell-signaling pathways were frequently reported in lymphomas. Among the altered pathways, perturbations of NFκB signaling play a significant role in lymphomagenesis. Specifically, the MYD88 L265P mutation, an activator of NFκB signaling, is extensively studied in intraocular lymphoma but not at other sites. Therefore, this study aims to screen the MYD88 L265P mutation in Ocular adnexal B cell lymphoma tumors and assess its clinical significance. METHODS AND RESULTS: Our study of twenty Ocular adnexal B cell lymphoma tumor samples by Allele-Specific Polymerase Chain Reaction identified two samples positive for the MYD88 L265P mutation. Subsequent Sanger sequencing confirmed the presence of the heterozygous mutation in those two samples tested positive in Allele-Specific Polymerase Chain Reaction. A comprehensive review of MYD88 L265P mutation in Ocular adnexal B cell lymphoma revealed variable frequencies, ranging from 0 to 36%. The clinical, pathological, and prognostic features showed no differences between patients with and without the MYD88 L265P mutation. CONCLUSION: The present study indicates that the MYD88 L265P mutation is relatively infrequent in our cohort, underscoring the need for further validation in additional cohorts.
Asunto(s)
Neoplasias del Ojo , Linfoma de Células B , Mutación , Factor 88 de Diferenciación Mieloide , Factor 88 de Diferenciación Mieloide/genética , Humanos , Femenino , Persona de Mediana Edad , Masculino , Linfoma de Células B/genética , Anciano , Neoplasias del Ojo/genética , Mutación/genética , Adulto , Alelos , Anciano de 80 o más AñosRESUMEN
Inflammation and fibrosis play important roles in diabetic kidney disease (DKD). Previous studies have shown that glucagon-like peptide-1 receptor (GLP-1R) agonists had renal protective effects. However, the mechanisms are not clear. The present study explored the effect of liraglutide (LR), a GLP-1R agonist, on the downregulation of glomerular inflammation and fibrosis in DKD by regulating the Toll-like receptor (TLR)4/myeloid differentiation marker 88 (MyD88)/nuclear factor κB (NF-κB) signaling pathway in mesangial cells (MCs). In vitro, rat MCs were cultured in high glucose (HG). We found that liraglutide treatment significantly reduced the HG-mediated activation of the TLR4/MYD88/NF-κB signaling pathway, extracellular matrix (ECM)-related proteins, and inflammatory factors. A combination of TLR4 inhibitor (TAK242) and liraglutide did not synergistically inhibit inflammatory factors and ECM proteins. Furthermore, in the presence of TLR4 siRNA, liraglutide significantly blunted HG-induced expression of fibronectin protein and inflammatory factors. Importantly, TLR4 selective agonist LPS or TLR4 overexpression eliminated the improvement effects of liraglutide on the HG-induced response. In vivo, administration of liraglutide for 8 wk significantly improved the glomerular damage in streptozotocin-induced diabetic mice and reduced the expression of TLR4/MYD88/NF-κB signaling proteins, ECM protein, and inflammatory factors in renal cortex. TLR4-/- diabetic mice showed significant amelioration in urine protein excretion rate, glomerular pathological damage, inflammation, and fibrosis. Liraglutide attenuated glomerular hypertrophy, renal fibrosis, and inflammatory response in TLR4-/- diabetic mice. Taken together, our findings suggest that TLR4/MYD88/NF-κB signaling is involved in the regulation of inflammatory response and ECM protein proliferation in DKD. Liraglutide alleviates inflammation and fibrosis by downregulating the TLR4/MYD88/NF-κB signaling pathway in MCs.NEW & NOTEWORTHY Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has renoprotective effect in diabetic kidney disease (DKD). In DKD, TLR4/MYD88/NF-κB signaling is involved in the regulation of inflammatory responses and extracellular matrix (ECM) protein proliferation. Liraglutide attenuates renal inflammation and overexpression of ECM proteins by inhibiting TLR4/MYD88/NF-κB signaling pathway. Therefore, we have identified a new mechanism that contributes to the renal protection of GLP-1RA, thus helping to design innovative treatment strategies for diabetic patients with various complications.
Asunto(s)
Diabetes Mellitus Experimental , Nefropatías Diabéticas , Fibrosis , Liraglutida , Factor 88 de Diferenciación Mieloide , FN-kappa B , Transducción de Señal , Receptor Toll-Like 4 , Animales , Liraglutida/farmacología , Liraglutida/uso terapéutico , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/metabolismo , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Masculino , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicaciones , Ratones , Ratones Endogámicos C57BL , Ratas , Regulación hacia Abajo/efectos de los fármacos , Ratas Sprague-Dawley , Células Mesangiales/efectos de los fármacos , Células Mesangiales/metabolismo , Células Mesangiales/patología , Ratones Noqueados , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéuticoRESUMEN
Cystic echinococcosis (CE) is a zoonotic disease caused by the parasite Echinococcus granulosus (E. granulosus), which can lead to the formation of liver lesions. Research indicates that E. granulosus releases both Toll-like receptor 2 (TLR2) and Interleukin-9 (IL-9), which can potentially impair the body's innate immune defenses and compromise the liver's ability to fight against diseases. To investigate the role of TLR2 and IL-9 in liver damage caused by E. granulosus infection, samples were initially collected from individuals diagnosed with CE. Subsequently, BALB/c mice were infected with E. granulosus at multiple time points (4 weeks, 12 weeks, 32 weeks) and the expression levels of these markers was then assessed at each of these phases. Furthermore, a BALB/c mouse model was generated and administered anti-IL-9 antibody via intraperitoneal injection. The subsequent analysis focused on the TLR2/MyD88/NF-κB signaling pathway and the expression of IL-9 in E. granulosus was examined. A co-culture experiment was conducted using mouse mononuclear macrophage cells (RAW264.7) and hepatic stellate cells (HSCs) in the presence of E. granulosus Protein (EgP). The findings indicated elevated levels of IL-9 and TLR2 in patients with CE, with the activation of the signaling pathway significantly increased as the duration of infection progressed. Administration of anti-IL-9 in mice reduced the activation of the TLR2/MyD88/NF-κB signaling pathway, exacerbating liver injury. Moreover, EgP stimulates the TLR2/MyD88/NF-κB signaling pathway, resulting in the synthesis of α-SMA and Collagen I. The data suggest that infection with E. granulosus may stimulate the production of IL-9 through the activation of the TLR2/MyD88/NF-κB signaling pathway, which is mediated by TLR2. This activation stimulates RAW264.7 and HSCs, exacerbating liver injury and fibrosis.
Asunto(s)
Equinococosis , Echinococcus granulosus , Interleucina-9 , Ratones Endogámicos BALB C , Factor 88 de Diferenciación Mieloide , Receptor Toll-Like 2 , Animales , Ratones , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 2/genética , Humanos , Equinococosis/patología , Equinococosis/inmunología , Equinococosis/metabolismo , Interleucina-9/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Células RAW 264.7 , Hígado/parasitología , Hígado/metabolismo , Hígado/patología , Femenino , Transducción de Señal , FN-kappa B/metabolismo , Masculino , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/parasitología , Adulto , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Tumor necrosis factor alpha induced protein 3 (TNFAIP3) is reportedly to have significant implications for autophagy regulation in various cancers. The current study aimed to decipher the role and mechanism of TNFAIP3 in diffuse large B-cell lymphoma (DLBCL) by modulating autophagy. METHODS: Information pertaining to the differential expression and prognostic role of TNFAIP3 in DLBCL was gleaned from the Gene Expression Omnibus (GEO) database. The TNFAIP3 expression levels in human DLBCL cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Cell counting kit-8 (CCK-8) and colony formation assays were employed to determine cell proliferation. Transwell assay and flow cytometry were applied to detect cell migration and apoptosis, respectively. Immunofluorescence and transmission electron microscope were used for the assessment of cell autophagy. The levels of apoptotic markers (caspase-3, cleaved-caspase-3, Bcl-2 Associated X (Bax), and B cell lymphoma-2 (Bcl-2)), autophagy indicators (the ratio of microtubule-associated proteins 1A/1B light chain 3 II and I (LC3II/LC3I), Sequestosome (p62)), and pathway proteins (toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), Transcription Factor NF-Kappa-B P65 Subunit (p65), and phosphorylated-p65 (p-p65)) were assessed via Western blotting. Immunohistochemistry was employed to detect Ki67 expression in tumor tissues. RESULTS: TNFAIP3 expression in DLBCL samples was downregulated, correlating with poor prognosis. TNFAIP3 expression was also downregulated in DLBCL cells. It was found that TNFAIP3 impeded cell proliferation and migration, and enhanced apoptosis of OCI-LY3 cells. Intervention with autophagy inhibitor 3-methyladenine (3-MA) markedly reversed apoptosis of OCI-LY3 cells induced by TNFAIP3. Besides, TNFAIP3 induced autophagy via modulating the TLR4/MyD88/nuclear factor kappa B (NF-κB) signaling pathway. In vivo experiments showed that TNFAIP3 expression in DLBCL was downregulated, and upregulation of TNFAIP3 could inhibit tumor growth. CONCLUSION: TNFAIP3 inhibits DLBCL progression by inducing TLR4/MyD88/NF-κB pathway-mediated autophagy.
Asunto(s)
Autofagia , Linfoma de Células B Grandes Difuso , Factor 88 de Diferenciación Mieloide , FN-kappa B , Transducción de Señal , Receptor Toll-Like 4 , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa , Humanos , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Autofagia/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , FN-kappa B/metabolismo , Línea Celular Tumoral , Animales , Regulación Neoplásica de la Expresión Génica , Ratones , Proliferación Celular , Apoptosis/genética , Masculino , Femenino , Progresión de la Enfermedad , Movimiento CelularRESUMEN
Nearly six million people worldwide have died from the coronavirus disease (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although COVID-19 vaccines are largely successful in reducing the severity of the disease and deaths, the decline in vaccine-induced immunity over time and the continuing emergence of new viral variants or mutations underscore the need for an alternative strategy for developing broad-spectrum host-mediated therapeutics against SARS-CoV-2. A key feature of severe COVID-19 is dysregulated innate immune signaling, culminating in a high expression of numerous pro-inflammatory cytokines and chemokines and a lack of antiviral interferons (IFNs), particularly type I (alpha and beta) and type III (lambda). As a natural host defense, the myeloid differentiation primary response protein, MyD88, plays pivotal roles in innate and acquired immune responses via the signal transduction pathways of Toll-like receptors (TLRs), a type of pathogen recognition receptors (PRRs). However, recent studies have highlighted that infection with viruses upregulates MyD88 expression and impairs the host antiviral response by negatively regulating type I IFN. Galectin-3 (Gal3), another key player in viral infections, has been shown to modulate the host immune response by regulating viral entry and activating TLRs, the NLRP3 inflammasome, and NF-κB, resulting in the release of pro-inflammatory cytokines and contributing to the overall inflammatory response, the so-called "cytokine storm". These studies suggest that the specific inhibition of MyD88 and Gal3 could be a promising therapy for COVID-19. This review presents future directions for MyD88- and Gal3-targeted antiviral drug discovery, highlighting the potential to restore host immunity in SARS-CoV-2 infections.
Asunto(s)
Antivirales , COVID-19 , Galectina 3 , Factor 88 de Diferenciación Mieloide , SARS-CoV-2 , Humanos , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , SARS-CoV-2/fisiología , SARS-CoV-2/inmunología , COVID-19/inmunología , COVID-19/virología , Antivirales/uso terapéutico , Antivirales/farmacología , Galectina 3/metabolismo , Tratamiento Farmacológico de COVID-19 , Inmunidad Innata , Transducción de Señal , AnimalesRESUMEN
Inflammation is the body's response to injuries, which depends on numerous regulatory factors. Among them, miRNAs have gained much attention for their role in regulating inflammatory gene expression at multiple levels. In particular, miR-21 is up-regulated during the inflammatory response and reported to be involved in the resolution of inflammation by down-regulating pro-inflammatory mediators, including MyD88. Herein, we evaluated the regulatory effects of miR-21 on the TLR-4/MyD88 pathway in an in vitro model of 6-mer HA oligosaccharides-induced inflammation in human chondrocytes. The exposition of chondrocytes to 6-mer HA induced the activation of the TLR4/MyD88 pathway, which culminates in NF-kB activation. Changes in miR-21, TLR-4, MyD88, NLRP3 inflammasome, IL-29, Caspase1, MMP-9, iNOS, and COX-2 mRNA expression of 6-mer HA-stimulated chondrocytes were examined by qRT-PCR. Protein amounts of TLR-4, MyD88, NLRP3 inflammasome, p-ERK1/2, p-AKT, IL-29, caspase1, MMP-9, p-NK-kB p65 subunit, and IKB-a have been evaluated by ELISA kits. NO and PGE2 levels have been assayed by colorimetric and ELISA kits, respectively. HA oligosaccharides induced a significant increase in the expression of the above parameters, including NF-kB activity. The use of a miR-21 mimic attenuated MyD88 expression levels and the downstream effectors. On the contrary, treatment with a miR-21 inhibitor induced opposite effects. Interestingly, the use of a MyD88 siRNA confirmed MyD88 as the target of miR-21 action. Our results suggest that miR-21 expression could increase in an attempt to reduce the inflammatory response, targeting MyD88.
Asunto(s)
Condrocitos , Ácido Hialurónico , Inflamación , MicroARNs , Factor 88 de Diferenciación Mieloide , Oligosacáridos , Humanos , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , MicroARNs/genética , MicroARNs/metabolismo , Condrocitos/metabolismo , Condrocitos/efectos de los fármacos , Ácido Hialurónico/farmacología , Ácido Hialurónico/metabolismo , Inflamación/metabolismo , Inflamación/genética , Oligosacáridos/farmacología , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Transducción de Señal/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , FN-kappa B/metabolismo , Células CultivadasRESUMEN
In this study, we investigated whether the ability of aucubin to mitigate the pathology of GONFH involves suppression of TLR4/NF-κB signalling and promotion of macrophage polarization to an M2 phenotype. In necrotic bone tissues from GONFH patients, we compared levels of pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages as well as levels of TLR4/NF-κB signalling. In a rat model of GONFH, we examined the effects of aucubin on these parameters. We further explored its mechanism of action in a cell culture model of M1 macrophages. Necrotic bone tissues from GONFH patients contained a significantly increased macrophage M1/M2 ratio, and higher levels of TLR4, MYD88 and NF-κB p65 than bone tissues from patients with hip osteoarthritis. Treating GONFH rats with aucubin mitigated bone necrosis and demineralization as well as destruction of trabecular bone and marrow in a dose-dependent manner, based on micro-computed tomography. These therapeutic effects were associated with a decrease in the overall number of macrophages, decrease in the proportion of M1 macrophages, increase in the proportion of M2 macrophages, and downregulation of TLR4, MYD88 and NF-κB p65. These effects in vivo were confirmed by treating cultures of M1 macrophage-like cells with aucubin. Aucubin mitigates bone pathology in GONFH by suppressing TLR4/NF-κB signalling to shift macrophages from a pro- to anti-inflammatory phenotype.
Asunto(s)
Glucósidos Iridoides , Macrófagos , Factor 88 de Diferenciación Mieloide , Transducción de Señal , Receptor Toll-Like 4 , Animales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ratas , Modelos Animales de Enfermedad , Necrosis de la Cabeza Femoral/inducido químicamente , Necrosis de la Cabeza Femoral/patología , Necrosis de la Cabeza Femoral/metabolismo , Necrosis de la Cabeza Femoral/tratamiento farmacológico , Glucocorticoides/farmacología , Glucósidos Iridoides/farmacología , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , FN-kappa B/metabolismo , Fenotipo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismoRESUMEN
Non-alcoholic fatty liver disease (NAFLD) not only could cause abnormal lipid metabolism in the liver, but also could cause liver inflammation. Previous studies have shown that Polysaccharide of Atractylodes macrocephala Koidz (PAMK) could alleviate animal liver inflammatory damage and alleviate NAFLD in mice caused by high-fat diet(HFD), but regulation of liver inflammation caused by NAFLD has rarely been reported. In this study, an animal model of non-alcoholic fatty liver inflammation in the liver of mice was established to explore the protective effect of PAMK on the liver of mice. The results showed that PAMK could alleviate the abnormal increase of body weight and liver weight of mice caused by HFD, alleviate the abnormal liver structure of mice, reduce the level of oxidative stress and cytokine secretion in the liver of mice, and downregulate the mRNA expression of TLR4, MyD88, NF-κB and protein expression of P-IκB, P-NF-κB-P65, TLR4, MyD88, NF-κB in the liver. These results indicate that PAMK could alleviate hepatocyte fatty degeneration and damage, oxidative stress and inflammatory response of the liver caused by NAFLD in mice.
Asunto(s)
Atractylodes , Dieta Alta en Grasa , Hígado , Factor 88 de Diferenciación Mieloide , FN-kappa B , Enfermedad del Hígado Graso no Alcohólico , Polisacáridos , Transducción de Señal , Receptor Toll-Like 4 , Animales , Atractylodes/química , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/inmunología , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Polisacáridos/farmacología , Polisacáridos/uso terapéutico , Ratones , Masculino , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Estrés Oxidativo/efectos de los fármacos , Modelos Animales de Enfermedad , Citocinas/metabolismo , Ratones Endogámicos C57BL , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacologíaRESUMEN
Neutrophils and macrophages confine pathogens by entrapping them in extracellular traps (ETs) through activating TLR9 function. However, plasmodial parasites secreted TatD-like DNases (TatD) to counteract ETs-mediated immune clearance. We found that TLR9 mutant mice increased susceptibility to rodent malaria, suggesting TLR9 is a key protein for host defense. We found that the proportion of neutrophils and macrophages in response to plasmodial parasite infection in the TLR9 mutant mice was significantly reduced compared to that of the WT mice. Importantly, PbTatD can directly bind to the surface TLR9 (sTLR9) on macrophages, which blocking the phosphorylation of mitogen-activated protein kinase and nuclear factor-κB, negatively regulated the signaling of ETs formation by both macrophages and neutrophils. Such, P. berghei TatD is a parasite virulence factor that can inhibit the proliferation of macrophages and neutrophils through directly binding to TLR9 receptors on the cell surface, thereby blocking the activation of the downstream MyD88-NF-kB pathways.
Asunto(s)
Desoxirribonucleasas , Inmunidad Innata , Macrófagos , Malaria , Neutrófilos , Plasmodium berghei , Transducción de Señal , Animales , Humanos , Ratones , Desoxirribonucleasas/metabolismo , Trampas Extracelulares/inmunología , Trampas Extracelulares/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Malaria/inmunología , Malaria/parasitología , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Neutrófilos/inmunología , FN-kappa B/metabolismo , Plasmodium berghei/inmunología , Proteínas Protozoarias/metabolismo , Proteínas Protozoarias/inmunología , Proteínas Protozoarias/genética , Receptor Toll-Like 9/metabolismoRESUMEN
The quest for targeted therapies is critical in the battle against cancer. The RAS/MAP kinase pathway is frequently implicated in neoplasia, with ERK playing a crucial role as the most distal kinase in the RAS signaling cascade. Our previous research demonstrated that the interaction between ERK and MYD88, an adaptor protein in innate immunity, is crucial for RAS-dependent transformation and cancer cell survival. In this study, we examine the biological consequences of disrupting the ERK-MYD88 interaction through the ERK D-recruitment site (DRS), while preserving ERK's kinase activity. Our results indicate that EI-52, a small-molecule benzimidazole targeting ERK-MYD88 interaction induces an HRI-mediated integrated stress response (ISR), resulting in immunogenic apoptosis specific to cancer cells. Additionally, EI-52 exhibits anti-tumor efficacy in patient-derived tumors and induces an anti-tumor T cell response in mice in vivo. These findings suggest that inhibiting the ERK-MYD88 interaction may be a promising therapeutic approach in cancer treatment.
Asunto(s)
Bencimidazoles , Quinasas MAP Reguladas por Señal Extracelular , Factor 88 de Diferenciación Mieloide , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Humanos , Animales , Ratones , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Línea Celular Tumoral , Bencimidazoles/farmacología , Apoptosis/efectos de los fármacos , Muerte Celular Inmunogénica/efectos de los fármacos , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/metabolismo , Femenino , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoAsunto(s)
Factor 88 de Diferenciación Mieloide , Receptores CXCR4 , Macroglobulinemia de Waldenström , Humanos , Macroglobulinemia de Waldenström/genética , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Masculino , Persona de Mediana Edad , Anciano , FemeninoRESUMEN
Both of exosomes derived from mesenchymal stem cells (MSCs) and glial cell line-derived neurotrophic factor (GDNF) show potential for the treatment of neuropathic pain. Here, the analgesic effects of exosomes derived from bone marrow MSCs (BMSCs) were investigated. BMSCs-derived exosomes were isolated and characterized. Chronic constriction injury (CCI) was constructed to induce neuropathic pain in rats, which were then treated with exosomes. Pain behaviors were evaluated by measuring paw withdrawal thresholds and latency. The changes of key proteins, including cytokines, were explored using Western blot and ELISA. Administration of BMSCs-derived exosomes alleviated neuropathic pain, as demonstrated by the decrease of thermal hyperalgesia and mechanical allodynia, as well as the reduced secretion of pro-inflammatory cytokines in CCI rats. These effects were comparable to the treatment of GDNF alone. Mechanically, the exosomes suppressed the CCI-induced activation of TLR2/MyD88/NF-κB signaling pathway, while GDNF knockdown impaired their analgesic effects on CCI rat. BMSCs-derived exosomes may alleviate CCI-induced neuropathic pain and inflammation in rats by transporting GDNF.
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Modelos Animales de Enfermedad , Exosomas , Factor Neurotrófico Derivado de la Línea Celular Glial , Hiperalgesia , Células Madre Mesenquimatosas , Factor 88 de Diferenciación Mieloide , FN-kappa B , Ratas Sprague-Dawley , Transducción de Señal , Receptor Toll-Like 2 , Animales , Exosomas/trasplante , Ratas , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Masculino , Hiperalgesia/etiología , Factor 88 de Diferenciación Mieloide/genética , FN-kappa B/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/biosíntesis , Neuralgia/etiología , Neuralgia/terapia , Citocinas , Trasplante de Células Madre Mesenquimatosas , Células de la Médula Ósea , Neuropatía Ciática , ConstricciónRESUMEN
The objective of this study was to investigate the impact of ethyl pyruvate (EP), an HMGB1 inhibitor, on ESCC cells both in vitro and in vivo. The viability of ESCC cells was assessed using the MTT method to evaluate the correlation between EP and cell viability. A scratch test was used to investigate the relationship between EP and cell migration and invasion. The effects of EP on tumor growth and survival in cancerous nude mice were examined using a tumor formation model. Immunohistochemical staining was performed to evaluate the expression levels of HMGB1, TLR4, and MyD88 in tumor tissues. EP, an anti-HMGB1 inhibitor, inhibited ESCC cell proliferation and metastasis in vitro and in vivo. Furthermore, compared with the control treatment, EP improved the activity, diet, and drinking behaviour of nude mice; inhibited tumour growth; and led to lower protein expression levels of HMGB1, TLR4, and MyD88. EP has the potential to regulate the HMGB1/TLR4-MyD88 signaling pathway, thereby inhibiting the proliferation and metastasis of ESCC, suppressing tumor growth, improving quality of life, and serving as an effective drug for ESCC treatment.
Asunto(s)
Carcinoma de Células Escamosas , Proliferación Celular , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Proteína HMGB1 , Ratones Desnudos , Factor 88 de Diferenciación Mieloide , Piruvatos , Receptor Toll-Like 4 , Animales , Piruvatos/farmacología , Humanos , Proteína HMGB1/metabolismo , Proteína HMGB1/genética , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Línea Celular Tumoral , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/metabolismo , Proliferación Celular/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Movimiento Celular/efectos de los fármacos , Ratones , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos BALB C , Supervivencia Celular/efectos de los fármacos , MasculinoRESUMEN
Myocardial ischaemia-reperfusion injury (MIRI) caused by the treatment of acute myocardial infarction (AMI) is the primary cause of severe ventricular remodelling, heart failure (HF), and high mortality. In recent studies, research on the role of necroptosis in MIRI has focused on cardiomyocytes, but new biomarkers and immunocyte mechanisms of necroptosis are rarely studied. In the present study, weighted gene co-expression network analysis (WGCNA) algorithms were used to establish a weighted gene co-expression network, and Casp1, Hpse, Myd88, Ripk1, and Tpm3 were identified as biological markers of necroptosis using least absolute shrinkage, selection operator (LASSO) regression and support vector machine (SVM) feature selection algorithms. The role and discriminatory power of these five genes in MIRI had never been studied. Single-cell and cell-talk analyses showed that hub genes of necroptosis were focused on macrophages, which mediate the functions of monocytes, fibroblasts, haematopoietic stem cells, and cardiomyocytes, primarily through the TNF/TNFRSF1A interaction. The polarisation and functional activation of macrophages were affected by the MIF signalling network (MIF CD74/CXCR4 and MIF CD74/CD44) of other cells. The results of the immune infiltration assay showed that the five genes involved in necroptosis were significantly related to the infiltration and functional activity of M2 macrophages. TWS-119 is predicted to be a molecular drug that targets key MIRI genes. A mouse model was established to confirm the expression of five hub genes, and ventricular remodelling increased with time after ischaemia-reperfusion injury (IRI). Therefore, Casp1, Hpse, Myd88, Ripk1, and Tpm3 may be key genes regulating necroptosis and polarisation in macrophages, and causing ventricular remodelling.