RESUMEN
Anticoccidial vaccines comprising living oocysts of Eimeria tenella, Eimeria necatrix, Eimeria maxima, and Eimeria acervulina are used to control coccidiosis. This study explored the potential of IL-1ß to act as a molecular adjuvant for enhancing the immunogenicity of Eimeria necatrix and mucosal immunity. We engineered E. necatrix to express a functional chIL-1ß (EnIL-1ß) and immunized chickens with oocysts of the wild type (EnWT) and tranegenic (EnIL-1ß) strains, respectively. The chickens were then challenged with EnWT oocysts to examine the immunogenicity-enhancing potential of chIL-1ß. As expected, the oocyst output of EnIL-1ß-immunized chickens was significantly reduced compared to those immunized using EnWT. No difference in body weight gain and lesion scores of EnIL-1ß and EnWT groups was observed. The parasite load in the small intestine and caeca showed that the invasion and replication of EnIL-1ß was not affected. However, the markers of immunogenicity and mucosal barrier, Claudin-1 and avian ß-defensin-1, were elevated in EnIL-1ß-infected chickens. Ectopic expression of chIL-1ß in E. necatrix thus appears to improve its immunogenicity and mucosal immunity, without increasing pathogenicity. Our findings support chIL-1ß as a candidate for development of effective live-oocyst-based anticoccidial vaccines.
Asunto(s)
Pollos , Coccidiosis , Eimeria , Inmunidad Mucosa , Interleucina-1beta , Enfermedades de las Aves de Corral , Vacunas Antiprotozoos , Animales , Coccidiosis/inmunología , Coccidiosis/veterinaria , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Pollos/inmunología , Eimeria/inmunología , Vacunas Antiprotozoos/inmunología , Enfermedades de las Aves de Corral/inmunología , Enfermedades de las Aves de Corral/parasitología , Enfermedades de las Aves de Corral/prevención & control , Inmunización , Oocistos/inmunología , Microorganismos Modificados GenéticamenteRESUMEN
This study aimed to investigate the effects of corn gluten-derived soluble epoxide hydrolase (sEH) inhibitory peptides on nonalcoholic fatty liver fibrosis induced by a high-fat diet and carbon tetrachloride in mice. Mice treated with corn peptides at doses of 500 or 1000 mg/kg/d for 4 weeks exhibited reduced sEH activity in serum and liver, enhanced lipid metabolism, and decreased lipid accumulation and oxidative stress. Corn peptides effectively downregulated the mRNA levels of Pro-IL-1ß, Pro-IL-18, NOD-like receptor protein 3 (NLRP3), ASC, Pro-caspase-1, Caspase-1, and GSDMD in the liver. This hepatoprotective effect of corn peptides by inhibiting NLRP3 inflammasome activation was further validated in H2O2-induced HepG2 cells. Moreover, corn peptides restored the composition of the gut microbiota and promoted short-chain fatty acid production. This study provides evidence that corn-derived sEH inhibitory peptides have hepatoprotective activity against nonalcoholic fatty liver fibrosis by suppressing NLRP3 inflammasome activation and modulating gut microbiota.
Asunto(s)
Microbioma Gastrointestinal , Inflamasomas , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Enfermedad del Hígado Graso no Alcohólico , Péptidos , Zea mays , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/inmunología , Ratones , Microbioma Gastrointestinal/efectos de los fármacos , Inflamasomas/metabolismo , Inflamasomas/genética , Masculino , Humanos , Zea mays/química , Péptidos/farmacología , Péptidos/administración & dosificación , Hígado/metabolismo , Hígado/efectos de los fármacos , Bacterias/clasificación , Bacterias/genética , Bacterias/efectos de los fármacos , Bacterias/aislamiento & purificación , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Células Hep G2 , Epóxido Hidrolasas/genética , Epóxido Hidrolasas/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismoRESUMEN
Salmonella enterica serovar Typhi (S. Typhi) causes typhoid fever, a systemic infection that affects millions of people worldwide. S. Typhi can invade and survive within host cells, such as intestinal epithelial cells and macrophages, by modulating their immune responses. However, the immunomodulatory capability of S. Typhi in relation to TolC-facilitated efflux pump function remains unclear. The role of TolC, an outer membrane protein that facilitates efflux pump function, in the invasion and immunomodulation of S. Typhi, was studied in human intestinal epithelial cells and macrophages. The tolC deletion mutant of S. Typhi was compared with the wild-type and its complemented strain in terms of their ability to invade epithelial cells, survive and induce cytotoxicity in macrophages, and elicit proinflammatory cytokine production in macrophages. The tolC mutant, which has a defective outer membrane, was impaired in invading epithelial cells compared to the wild-type strain, but the intracellular presence of the tolC mutant exhibited greater cytotoxicity and induced higher levels of proinflammatory cytokines (IL-1ß and IL-8) in macrophages compared to the wild-type strain. These effects were reversed by complementing the tolC mutant with a functional tolC gene. Our results suggest that TolC plays a role in S. Typhi to efficiently invade epithelial cells and suppress host immune responses during infection. TolC may be a potential target for the development of novel therapeutics against typhoid fever.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa , Células Epiteliales , Macrófagos , Salmonella typhi , Fiebre Tifoidea , Salmonella typhi/patogenicidad , Salmonella typhi/inmunología , Salmonella typhi/genética , Humanos , Macrófagos/microbiología , Macrófagos/inmunología , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/metabolismo , Proteínas de la Membrana Bacteriana Externa/inmunología , Células Epiteliales/microbiología , Células Epiteliales/inmunología , Fiebre Tifoidea/inmunología , Fiebre Tifoidea/microbiología , Inmunomodulación , Citocinas/metabolismo , Citocinas/inmunología , Viabilidad Microbiana , Interleucina-8/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/inmunología , Línea CelularRESUMEN
The Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome has been the most distinctive polymer protein complex. After recognizing the endogenous and exogenous danger signals, NLRP3 can cause inflammation by pyroptosis and secretion of mature, bioactive forms of IL-1ß and IL-18. The NLRP3 inflammasome is essential in the genesis and progression of infectious illnesses. Herein, we provide a comprehensive review of the NLRP3 inflammasome in infectious diseases, focusing on its two-sided effects. As an essential part of host defense with a protective impact, abnormal NLRP3 inflammasome activation, however, result in a systemic high inflammatory response, leading to subsequent damage. In addition, scientific evidence of small molecules, biologics, and phytochemicals acting on the NLRP3 inflammasome has been reviewed. We believe that the NLRP3 inflammasome helps us understand the pathological mechanism of different stages of infectious diseases and that inhibitors targeting the NLRP3 inflammasome will become a new and valuable research direction for the treatment of infectious diseases.
Asunto(s)
Enfermedades Transmisibles , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Humanos , Inflamasomas/inmunología , Inflamasomas/metabolismo , Animales , Enfermedades Transmisibles/inmunología , Enfermedades Transmisibles/metabolismo , Inflamación/inmunología , Interleucina-1beta/metabolismo , Interleucina-1beta/inmunologíaRESUMEN
Chronic inflammasome activation in mononuclear phagocytes (MNPs) promotes fibrosis in various tissues, including the kidney. The cellular and molecular links between the inflammasome and fibrosis are unclear. To address this question, we fed mice lacking various immunological mediators an adenine-enriched diet, which causes crystal precipitation in renal tubules, crystal-induced inflammasome activation, and renal fibrosis. We found that kidney fibrosis depended on an intrarenal inflammasome-dependent type 3 immune response driven by its signature transcription factor Rorc (retinoic acid receptor-related orphan receptor C gene), which was partially carried out by type 3 innate lymphoid cells (ILC3s). The role of ILCs in the kidney is less well known than in other organs, especially that of ILC3. In this article, we describe that depletion of ILCs or genetic deficiency for Rorc attenuated kidney inflammation and fibrosis. Among the inflammasome-derived cytokines, only IL-1ß expanded ILC3 and promoted fibrosis, whereas IL-18 caused differentiation of NKp46+ ILC3. Deficiency of the type 3 maintenance cytokine, IL-23, was more protective than IL-1ß inhibition, which may be explained by the downregulation of the IL-1R, but not of the IL-23R, by ILC3 early in the disease, allowing persistent sensing of IL-23. Mechanistically, ILC3s colocalized with renal MNPs in vivo as shown by multiepitope-ligand cartography. Cell culture experiments indicated that renal ILC3s caused renal MNPs to increase TGF-ß production that stimulated fibroblasts to produce collagen. We conclude that ILC3s link inflammasome activation with kidney inflammation and fibrosis and are regulated by IL-1ß and IL-23.
Asunto(s)
Fibrosis , Inmunidad Innata , Inflamasomas , Interleucina-23 , Linfocitos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Animales , Ratones , Inflamasomas/inmunología , Inflamasomas/metabolismo , Inmunidad Innata/inmunología , Linfocitos/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Interleucina-23/inmunología , Interleucina-23/metabolismo , Riñón/inmunología , Riñón/patología , Ratones Noqueados , Ratones Endogámicos C57BL , Enfermedades Renales/inmunología , Enfermedades Renales/patología , Interleucina-1beta/metabolismo , Interleucina-1beta/inmunologíaRESUMEN
Dendritic cells (DCs) are crucial for initiating the acquired immune response to infectious diseases such as tuberculosis. Mycobacterium tuberculosis has evolved strategies to inhibit activation of the NLRP3 inflammasome in macrophages via its serine/threonine protein kinase, protein kinase F (PknF). It is not known whether this pathway is conserved in DCs. In this study, we show that the pknF deletion mutant of M. tuberculosis (MtbΔpknF) compared with wild-type M. tuberculosis-infected cells induces increased production of IL-1ß and increased pyroptosis in murine bone marrow-derived DCs (BMDCs). As shown for murine macrophages, the enhanced production of IL-1ß postinfection of BMDCs with MtbΔpknF is dependent on NLRP3, ASC, and caspase-1/11. In contrast to macrophages, we show that MtbΔpknF mediates RIPK3/caspase-8-dependent IL-1ß production in BMDCs. Consistently, infection with MtbΔpknF results in increased activation of caspase-1 and caspase-8 in BMDCs. When compared with M. tuberculosis-infected cells, the IL-6 production by MtbΔpknF-infected cells was unchanged, indicating that the mutant does not affect the priming phase of inflammasome activation. In contrast, the activation phase was impacted because the MtbΔpknF-induced inflammasome activation in BMDCs depended on potassium efflux, chloride efflux, reactive oxygen species generation, and calcium influx. In conclusion, PknF is important for M. tuberculosis to evade NLRP3 inflammasome-mediated activation of caspase-1 and RIPK3/caspase-8 pathways in BMDCs.
Asunto(s)
Caspasa 1 , Caspasa 8 , Células Dendríticas , Inflamasomas , Interleucina-1beta , Mycobacterium tuberculosis , Proteína con Dominio Pirina 3 de la Familia NLR , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Ratones , Inflamasomas/inmunología , Inflamasomas/metabolismo , Caspasa 8/metabolismo , Caspasa 8/inmunología , Células Dendríticas/inmunología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/inmunología , Mycobacterium tuberculosis/inmunología , Caspasa 1/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/inmunología , Ratones Endogámicos C57BL , Tuberculosis/inmunología , Ratones Noqueados , Macrófagos/inmunología , Macrófagos/metabolismoRESUMEN
BACKGROUND: Investigation of the inflammatory response of immune cells is a current focus of research on autoimmune disorders. The aim of this study was to evaluate the inflammatory status of monocytes/macrophages in systemic sclerosis (SSc). METHODS: The study included 35 SSc and 25 healthy participants. The secretion of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), interleukin-6 (IL-6) was measured by enzyme-linked immunosorbent assay (ELISA) in primary cultures of monocytes/macrophages after stimulation with lipopolysaccharide (LPS) on day 1 and on day 6 of incubation. Impaired tolerance of the immune response was characterized by increased secretion of the inflammatory mediators in response to restimulation. RESULTS: Basal secretion of all cytokines was significantly higher in SSc patients compared to healthy individuals. The secretion of TNF-α, IL-1ß and IL-6 after the initial LPS stimulation, and secretion of IL-1ß, MCP-1, IL-6, IL-8 after LPS restimulation, was significantly higher in the SSc group. Eleven SSc patients (31%) showed impaired immune tolerance in terms of MCP-1 secretion. These patients were significantly younger and had a higher level of anti-topoisomerase I (anti-Scl70) antibodies compared to SSc patients with immune tolerance. CONCLUSIONS: This study revealed pro-inflammatory activation and impaired immune tolerance in monocytes/macrophages from SSc patients. The violation of immune response in terms of MCP-1 secretion may be an important factor in the development of chronic inflammation in SSc. MCP-1 may thus be a potential therapeutic target for novel SSc treatment strategies.
Asunto(s)
Macrófagos , Monocitos , Esclerodermia Sistémica , Humanos , Esclerodermia Sistémica/inmunología , Esclerodermia Sistémica/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Femenino , Masculino , Persona de Mediana Edad , Macrófagos/inmunología , Macrófagos/metabolismo , Adulto , Inflamación/inmunología , Lipopolisacáridos , Citocinas/metabolismo , Citocinas/inmunología , Estudios de Casos y Controles , Quimiocina CCL2/metabolismo , Quimiocina CCL2/inmunología , Anciano , Ensayo de Inmunoadsorción Enzimática , Interleucina-1beta/metabolismo , Interleucina-1beta/inmunologíaRESUMEN
Interleukin-1ß (IL-1ß) is one of the key mediators of inflammation during innate immune responses. Mature bioactive IL-1ß mediates essential host defense mechanisms but also has a mechanistic role in several autoinflammatory and degenerative diseases. In horses, specific and sensitive assays for IL-1ß are crucial for immunological research on inflammatory processes and diseases. In this article, we describe the development of four monoclonal antibodies (mAbs) against equine IL-1ß. The specificity of the new IL-1ß mAbs was confirmed using a panel of equine recombinant cytokines and chemokines. The mAbs were validated for detection of native mature IL-1ß in a fluorescent bead-based assay and for staining of IL-1ß-producing immune cells by flow cytometry. The bead-based assay for equine IL-1ß had a linear quantification range between 60â¯pg/ml to 960â¯ng/ml. Horse peripheral blood mononuclear cells (PBMC) secreted IL-1ß after lipopolysaccharide (LPS) stimulation in time and dose dependent manner as quantified by the new equine IL-1ß bead-based assay. A comparison of two commercial equine IL-1ß ELISA kits with the new IL-1ß fluorescent bead-based assay revealed that the bead-based assay improved the quantification of native equine IL-1ß in LPS stimulated PBMC supernatants by detecting it with high intensity and a broad linear quantification range, while both ELISAs resulted in low signals and poor native IL-1ß recognition. Intracellular staining and flow cytometric analysis confirmed that the main cellular source of IL-1ß in equine PBMC after LPS stimulation were CD14+ monocytes. IL-1ß secretion from PBMC was inhibited by a caspase inhibitor but protein translation within the cells was not, supporting the accumulation of pro-IL-1ß within the cells even when proteolytic cleavage for IL-1ß activation is missing. This confirmed the importance of specific mAbs for analyzing the biologically active, mature IL-1ß in horses.
Asunto(s)
Anticuerpos Monoclonales , Citometría de Flujo , Interleucina-1beta , Leucocitos Mononucleares , Animales , Ratones , Anticuerpos Monoclonales/inmunología , Ensayo de Inmunoadsorción Enzimática/veterinaria , Citometría de Flujo/veterinaria , Caballos/inmunología , Interleucina-1beta/inmunología , Leucocitos Mononucleares/inmunología , LipopolisacáridosRESUMEN
Up to 25% of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit postacute cognitive sequelae. Although millions of cases of coronavirus disease 2019 (COVID-19)-mediated memory dysfunction are accumulating worldwide, the underlying mechanisms and how vaccination lowers risk are unknown. Interleukin-1 (IL-1), a key component of innate immune defense against SARS-CoV-2 infection, is elevated in the hippocampi of individuals with COVID-19. Here we show that intranasal infection of C57BL/6J mice with SARS-CoV-2 Beta variant leads to central nervous system infiltration of Ly6Chi monocytes and microglial activation. Accordingly, SARS-CoV-2, but not H1N1 influenza virus, increases levels of brain IL-1ß and induces persistent IL-1R1-mediated loss of hippocampal neurogenesis, which promotes postacute cognitive deficits. Vaccination with a low dose of adenoviral-vectored spike protein prevents hippocampal production of IL-1ß during breakthrough SARS-CoV-2 infection, loss of neurogenesis and subsequent memory deficits. Our study identifies IL-1ß as one potential mechanism driving SARS-CoV-2-induced cognitive impairment in a new mouse model that is prevented by vaccination.
Asunto(s)
COVID-19 , Hipocampo , Interleucina-1beta , Trastornos de la Memoria , Ratones Endogámicos C57BL , Neurogénesis , SARS-CoV-2 , Animales , Interleucina-1beta/metabolismo , Interleucina-1beta/inmunología , Ratones , COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2/inmunología , Hipocampo/inmunología , Hipocampo/metabolismo , Trastornos de la Memoria/inmunología , Neurogénesis/inmunología , Vacunación , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunas contra la COVID-19/inmunología , Masculino , Humanos , Microglía/inmunología , Microglía/metabolismo , Modelos Animales de Enfermedad , Receptores Tipo I de Interleucina-1/metabolismo , Receptores Tipo I de Interleucina-1/genética , Monocitos/inmunología , Monocitos/metabolismo , FemeninoRESUMEN
Atractylodes macrocephala Koidz, a traditional Chinese medicine, contains atractylenolide I (ATR-I), which has potential anticancer, anti-inflammatory, and immune-modulating properties. This study evaluated the therapeutic potential of ATR-I for indomethacin (IND)-induced gastric mucosal lesions and its underlying mechanisms. Noticeable improvements were observed in the histological morphology and ultrastructures of the rat gastric mucosa after ATR-I treatment. There was improved blood flow, a significant decrease in the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1ß, and IL-18, and a marked increase in prostaglandin E2 (PGE2) expression in ATR-I-treated rats. Furthermore, there was a significant decrease in the mRNA and protein expression levels of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), cysteinyl aspartate specific proteinase-1 (caspase-1), and nuclear factor-κB (NF-κB) in rats treated with ATR-I. The results show that ATR-I inhibits the NLRP3 inflammasome signaling pathway and effectively alleviates local inflammation, thereby improving the therapeutic outcomes against IND-induced gastric ulcers in rats.
Asunto(s)
Atractylodes , Mucosa Gástrica , Indometacina , Inflamasomas , Lactonas , Proteína con Dominio Pirina 3 de la Familia NLR , Ratas Sprague-Dawley , Sesquiterpenos , Úlcera Gástrica , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Indometacina/efectos adversos , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/metabolismo , Ratas , Sesquiterpenos/farmacología , Sesquiterpenos/química , Lactonas/farmacología , Lactonas/química , Inflamasomas/metabolismo , Inflamasomas/genética , Inflamasomas/efectos de los fármacos , Masculino , Atractylodes/química , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Humanos , FN-kappa B/genética , FN-kappa B/metabolismo , FN-kappa B/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/inmunología , Caspasa 1/genética , Caspasa 1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-6/inmunología , Interleucina-18/genética , Interleucina-18/metabolismoRESUMEN
The inflammasome is a multimeric protein complex that plays a vital role in the defence against pathogens and is therefore considered an essential component of the innate immune system. In this study, the expression patterns of inflammasome genes (NLRC3, ASC, and CAS-1), antiviral genes (IFNγ and MX), and immune genes (IL-1ß and IL-18) were analysed in Oreochromis niloticus liver (ONIL) cells following stimulation with the bacterial ligands peptidoglycan (PGN) and lipopolysaccharide (LPS) and infection with TiLV. The cells were stimulated with PGN and LPS at concentrations of 10, 25, and 50 µg/ml. For viral infection, 106 TCID50 of TiLV per ml was used. After LPS stimulation, all seven genes were found to be expressed at specific time points at each of the three doses tested. However, at even higher doses of LPS, NLRC3 levels decreased. Following TiLV infection, all of the genes showed significant upregulation, especially at early time points. However, the gene expression pattern was found to be unique in PGN-treated cells. For instance, NLRC3 and ASC did not show any response to PGN stimulation, and the expression of IFNγ was downregulated at 25 and 50 µg of PGN per ml. CAS-1 and IL-18 expression was downregulated at 25 µg of PGN per ml. At a higher dose (50 µg/ml), IL-1ß showed downregulation. Overall, our results indicate that these genes are involved in the immune response to viral and bacterial infection and that the degree of response is ligand- and dose-dependent.
Asunto(s)
Cíclidos , Enfermedades de los Peces , Inflamasomas , Animales , Cíclidos/inmunología , Cíclidos/genética , Inflamasomas/genética , Inflamasomas/inmunología , Inflamasomas/metabolismo , Enfermedades de los Peces/inmunología , Enfermedades de los Peces/virología , Enfermedades de los Peces/microbiología , Enfermedades de los Peces/genética , Línea Celular , Peptidoglicano/farmacología , Hígado/virología , Hígado/inmunología , Lipopolisacáridos/farmacología , Inmunidad Innata , Proteínas de Peces/genética , Interleucina-18/genética , Interleucina-18/metabolismo , Ligandos , Infecciones por Virus ADN/inmunología , Infecciones por Virus ADN/veterinaria , Infecciones por Virus ADN/virología , Infecciones por Virus ADN/genética , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/inmunologíaRESUMEN
While inflammation is beneficial for insulin secretion during homeostasis, its transformation adversely affects ß cells and contributes to diabetes. However, the regulation of islet inflammation for maintaining glucose homeostasis remains largely unknown. Here, we identified pericytes as pivotal regulators of islet immune and ß cell function in health. Islets and pancreatic pericytes express various cytokines in healthy humans and mice. To interfere with the pericytic inflammatory response, we selectively inhibited the TLR/MyD88 pathway in these cells in transgenic mice. The loss of MyD88 impaired pericytic cytokine production. Furthermore, MyD88-deficient mice exhibited skewed islet inflammation with fewer cells, an impaired macrophage phenotype, and reduced IL-1ß production. This aberrant pericyte-orchestrated islet inflammation was associated with ß cell dedifferentiation and impaired glucose response. Additionally, we found that Cxcl1, a pericytic MyD88-dependent cytokine, promoted immune IL-1ß production. Treatment with either Cxcl1 or IL-1ß restored the mature ß cell phenotype and glucose response in transgenic mice, suggesting a potential mechanism through which pericytes and immune cells regulate glucose homeostasis. Our study revealed pericyte-orchestrated islet inflammation as a crucial element in glucose regulation, implicating this process as a potential therapeutic target for diabetes.
Asunto(s)
Inflamación , Interleucina-1beta , Factor 88 de Diferenciación Mieloide , Pericitos , Transducción de Señal , Animales , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Ratones , Pericitos/metabolismo , Pericitos/patología , Pericitos/inmunología , Humanos , Inflamación/patología , Inflamación/metabolismo , Inflamación/genética , Inflamación/inmunología , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Ratones Transgénicos , Receptores Toll-Like/metabolismo , Receptores Toll-Like/genética , Quimiocina CXCL1/metabolismo , Quimiocina CXCL1/genética , Islotes Pancreáticos/inmunología , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Ratones Noqueados , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Células Secretoras de Insulina/inmunología , Masculino , Glucosa/metabolismoRESUMEN
Introduction: Antibody production and the generation of memory B cells are regulated by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells in germinal centers. However, the precise role of Tfr cells in controlling antibody production is still unclear. We have previously shown that both Tfh and Tfr cells express the IL-1R1 agonist receptor, whereas only Tfr cells express the IL-1R2 decoy and IL-1Ra antagonist receptors. We aimed to investigate the role of IL-1 receptors in the regulation of B cell responses by Tfh and Tfr. Methods: We generated mice with IL-1 receptors inactivated in Tfh or Tfr and measured antibody production and cell activation after immunisation. Results: While IL-1ß levels are increased in the draining lymph node after immunisation, antigen-specific antibody levels and cell phenotypes indicated that IL-1ß can activate both Tfh and Tfr cells through IL-1R1 stimulation. Surprisingly, expression of IL-1R2 and IL-1Ra on Tfr cells does not block IL-1 activation of Tfh cells, but rather prevents IL-1/IL-1R1-mediated early activation of Tfr cells. IL-1Rs also regulate the antibody response to autoantigens and its associated pathophysiology in an experimental lupus model. Discussion: Collectively, our results show that IL-1 inhibitory receptors expressed by Tfr cells prevent their own activation and suppressive function, thus licensing IL-1-mediated activation of Tfh cells after immunisation. Further mechanistic studies should unravel these complex interactions between IL-1ß and follicular helper and regulatory T cells and provide new avenues for therapeutic intervention.
Asunto(s)
Centro Germinal , Células T Auxiliares Foliculares , Linfocitos T Reguladores , Animales , Centro Germinal/inmunología , Ratones , Células T Auxiliares Foliculares/inmunología , Linfocitos T Reguladores/inmunología , Activación de Linfocitos/inmunología , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/inmunología , Ratones Endogámicos C57BL , Linfocitos B/inmunología , Linfocitos B/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/inmunología , Interleucina-1/metabolismo , Interleucina-1/inmunología , Receptores de Interleucina-1/metabolismo , Receptores de Interleucina-1/inmunología , Formación de Anticuerpos/inmunologíaRESUMEN
This study aimed to explore the ameliorative effects and potential mechanisms of Huangshan Umbilicaria esculenta polysaccharide (UEP) in dextran sulfate sodium-induced acute ulcerative colitis (UC) and UC secondary liver injury (SLI). Results showed that UEP could ameliorate both colon and liver pathologic injuries, upregulate mouse intestinal tight junction proteins (TJs) and MUC2 expression, and reduce LPS exposure, thereby attenuating the effects of the gut-liver axis. Importantly, UEP significantly downregulated the secretion levels of TNF-α, IL-1ß, and IL-6 through inhibition of the NF-κB pathway and activated the Nrf2 signaling pathway to increase the expression levels of SOD and GSH-Px. In vitro, UEP inhibited the LPS-induced phosphorylation of NF-κB P65 and promoted nuclear translocation of Nrf2 in RAW264.7 cells. These results revealed that UEP ameliorated UC and SLI through NF-κB and Nrf2-mediated inflammation and oxidative stress. The study first investigated the anticolitis effect of UEP, suggesting its potential for the treatment of colitis and colitis-associated liver disease.
Asunto(s)
Colitis , Sulfato de Dextran , Factor 2 Relacionado con NF-E2 , FN-kappa B , Polisacáridos , Animales , Ratones , Polisacáridos/farmacología , Polisacáridos/química , Polisacáridos/administración & dosificación , Sulfato de Dextran/efectos adversos , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Humanos , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/metabolismo , Células RAW 264.7 , FN-kappa B/metabolismo , FN-kappa B/genética , Ratones Endogámicos C57BL , Sustancias Protectoras/farmacología , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/química , Hígado/efectos de los fármacos , Hígado/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Estrés Oxidativo/efectos de los fármacos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/inmunología , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-6/inmunología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/inducido químicamente , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Mucina 2/genética , Mucina 2/metabolismoRESUMEN
Steroid resistance poses a major challenge for the management of autoimmune neuroinflammation. T helper 17 (TH17) cells are widely implicated in the pathology of steroid resistance; however, the underlying mechanisms are unknown. In this study, we identified that interleukin-1 receptor (IL-1R) blockade rendered experimental autoimmune encephalomyelitis (EAE) mice sensitive to dexamethasone (Dex) treatment. Interleukin-1ß (IL-1ß) induced a signal transducer and activator of transcription 5 (STAT5)-mediated steroid-resistant transcriptional program in TH17 cells, which promoted inflammatory cytokine production and suppressed Dex-induced anti-inflammatory genes. TH17-specific deletion of STAT5 ablated the IL-1ß-induced steroid-resistant transcriptional program and rendered EAE mice sensitive to Dex treatment. IL-1ß synergized with Dex to promote the STAT5-dependent expression of CD69 and the development of central nervous system (CNS)-resident CD69+ TH17 cells. Combined IL-1R blockade and Dex treatment ablated CNS-resident TH17 cells, reduced EAE severity, and prevented relapse. CD69+ tissue-resident TH17 cells were also detected in brain lesions of patients with multiple sclerosis. These findings (i) demonstrate that IL-1ß-STAT5 signaling in TH17 cells mediates steroid resistance and (ii) identify a therapeutic strategy for reversing steroid resistance in TH17-mediated CNS autoimmunity.
Asunto(s)
Dexametasona , Encefalomielitis Autoinmune Experimental , Interleucina-1beta , Factor de Transcripción STAT5 , Células Th17 , Animales , Células Th17/inmunología , Factor de Transcripción STAT5/metabolismo , Factor de Transcripción STAT5/inmunología , Ratones , Interleucina-1beta/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Dexametasona/farmacología , Dexametasona/uso terapéutico , Ratones Endogámicos C57BL , Resistencia a Medicamentos , Transducción de Señal/inmunología , Ratones Noqueados , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Femenino , HumanosRESUMEN
This study deciphered the ameliorating effect and molecular mechanism of the total glucosides of White Paeony Capsules(TGP) in the treatment of mice model with acute lung injury(ALI) via NOD-like receptor thermal protein domain associated protein 3(NLRP3) signaling pathway of the inflammasome. The study established an inflammasome activation model of primed bone marrow-derived macrophages(BMDMs), and its molecular mechanism was investigated by Western blot(WB), immunofluorescence staining, enzyme-linked immunosorbent assay(ELISA), and flow cytometry. C57BL/6J mice were randomly divided into a blank control group, a TGP group, a model group(LPS group), LPS+low-and high-dose TGP groups, LPS+MCC950 group, and LPS+MCC950+TGP group, with eight mice per group. The ALI model was induced in mice. Finally, bronchoalveolar lavage fluid(BALF) and lung tissue were collected. Lung index and lung weight wet-to-dry ratio were determined for each group of mice. The pathological changes in lung tissue were observed through hematoxylin-eosin(HE) staining. The number of neutrophils in the BALF of each group was detected using flow cytometry. The levels of interleukin(IL)-1ß, IL-6, and tumor necrosis factor(TNF)-α in the BALF were determined by ELISA. The expressions of IL-1ß, IL-18, IL-6, and TNF-α in the lung tissue were determined by real-time quantitative PCR(RT-qPCR). This study demonstrated that TGP dramatically blocked the activation of the NLRP3 inflammasome by inhibiting the production of upstream mitochondrial reactive oxygen species(mtROS) and the subsequent oligomerization of apoptosis-associated specks(ASC). Additionally, in the ALI mice model, compared with the blank control group, the model group showed alveolar structure rupture, thic-kening of alveolar septa, and dramatically increased lung index, lung weight wet-to-dry ratio in lung tissue, neutrophil count, and inflammatory factor levels. Compared with the model group, the pathological morphology of lung tissue was significantly ameliorated in the TGP and MCC950 groups, and the lung index and lung weight wet-to-dry ratio were significantly reduced. Neutrophil counts were reduced, and levels of inflammatory factors were significantly downregulated. Notably, compared with the MCC950 group, there was no significant difference in effect in the MCC950+TGP group. Collectively, the study reveals that TGP may ameliorate ALI in mice by inhibiting the activation of NLRP3 inflammasome, providing a safe and effective drug candidate for the prevention or treatment of ALI/ARDS.
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Lesión Pulmonar Aguda , Medicamentos Herbarios Chinos , Glucósidos , Inflamasomas , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Paeonia , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Glucósidos/farmacología , Glucósidos/química , Ratones , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Masculino , Paeonia/química , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Cápsulas , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , Humanos , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismoRESUMEN
Interleukin-1ß (IL-1ß) contributes to interstitial lung disease (ILD) and pulmonary fibrosis (PF), thus representing a potential therapeutic target for PF. In this study, we first verified the increased expression of IL-1ß in human fibrotic lung specimens and mouse lung tissues after intratracheal (i.t.) instillation of bleomycin (BLM), after which the pro-inflammatory and pro-fibrotic effects of recombinant IL-1ß were tested in mice. The results above suggested that vaccination against IL-1ß could be an effective strategy for managing PF. An anti-IL-1ß vaccine (PfTrx-IL-1ß) was designed by incorporating two IL-1ß-derived polypeptides, which have been verified as the key domains that mediate the binding of IL-1ß to its type I receptor, into Pyrococcus furiosus thioredoxin (PfTrx). The fusion protein PfTrx-IL-1ß was prepared by using E. coli expression system. The vaccine was well tolerated; it induced robust and long-lasting antibody responses in mice and neutralized the biological activity of IL-1ß, as shown in cellular assays. Pre-immunization with PfTrx-IL-1ß effectively protected mice from BLM-induced lung injury, inflammation, and fibrosis. In vitro experiments further showed that anti-PfTrx-IL-1ß antibodies counteracted the effects of IL-1ß concerning pro-inflammatory and pro-fibrotic cytokine production by primary mouse lung fibroblast, macrophages (RAW264.7), and type II alveolar epithelial cell (A549), primary mouse lung fibroblast activation and epithelial-mesenchymal transition (EMT) of alveolar epithelial cells. In addition, the vaccination did not compromise the anti-infection immunity in mice, as validated by a sepsis model. Our preliminary study suggests that the anti-IL-1ß vaccine we prepared has the potential to be developed as a therapeutic measure for PF. Further experiments are warranted to evaluate whether IL-1ß vaccination has the capacity of inhibiting chronic progressive PF and reversing established PF.
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Bleomicina , Interleucina-1beta , Fibrosis Pulmonar , Animales , Fibrosis Pulmonar/prevención & control , Fibrosis Pulmonar/inmunología , Fibrosis Pulmonar/inducido químicamente , Interleucina-1beta/inmunología , Ratones , Humanos , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/administración & dosificación , Pulmón/patología , Pulmón/inmunología , Modelos Animales de Enfermedad , Femenino , Ratones Endogámicos C57BL , Proteínas Recombinantes de Fusión/inmunología , Tiorredoxinas/inmunologíaRESUMEN
Background: An increased level of interleukin-17A and interleukin-18 in the serum and intestinal mucosa of celiac disease patients reflecting the severity of villous atrophy and inflammation was documented. Thus, the objective of this study was to evaluate the concentrations of salivary-17A, interleukin-1 beta, and interleukin-18 in patients with celiac disease who are on a gluten-free diet, both with and without periodontitis, and to compare these levels with those in healthy individuals. Methods: The study involved 23 participants with serologically confirmed celiac disease (CD) and 23 control subjects. The CD patients had been following a gluten-free diet (GFD) for a minimum of 1 year and had no other autoimmune disorders. The research involved collecting demographic data, conducting periodontal examinations, gathering unstimulated whole saliva, and performing enzyme-linked immunosorbent assays to measure salivary interleukin-17A, interleukin-1 beta, and interleukin-18 levels. Spearman's correlation analysis was utilized to explore the relationships between CD markers in patients on a GFD and their periodontal clinical findings. Results: The periodontal findings indicated significantly lower values in celiac disease patients adhering to a gluten-free diet compared to control subjects (p = 0.001). No significant differences were found in salivary IL-17A, IL-18, and IL-1B levels between celiac disease patients and control subjects. Nevertheless, the levels of all interleukins were elevated in periodontitis patients in both the celiac and control groups. The IL-1 Beta level was significantly higher in periodontitis patients compared to non-periodontitis patients in the control group (p = 0.035). Significant negative correlations were observed between serum IgA levels and plaque index (r = -0.460, p = 0.010), as well as gingival index (r = -0.396, p = 0.030) in CD patients on a gluten-free diet. Conclusion: Celiac disease patients on gluten-free diet exhibited better periodontal health compared to control subjects. However, increased levels of salivary IL-17A, IL-18 and IL-1B levels were associated with periodontitis. Additionally, serum IgA level was significantly inversely associated with periodontitis clinical manifestations and with salivary inflammatory mediators in CD patients on GFD.
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Enfermedad Celíaca , Interleucina-17 , Interleucina-18 , Periodontitis , Saliva , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Biomarcadores/metabolismo , Estudios de Casos y Controles , Enfermedad Celíaca/inmunología , Dieta Sin Gluten , Interleucina-17/inmunología , Interleucina-18/inmunología , Interleucina-1beta/inmunología , Periodontitis/inmunología , Saliva/química , Saliva/inmunologíaRESUMEN
Among 5 types of the Christie-Atkins-Munch-Petersen factor (CAMP) of Cutibacterium acnes, CAMP1 is highly expressed in phylotype II as well as IB, and thought to be a virulence factor of opportunistic but fatal blood, soft tissue, and implant-related infections. The target of a human single-chain variable antibody fragment (scFv), recently isolated from a phage display library, has been identified as CAMP1 of phylotype II, using immunoprecipitation followed by mass spectrometry, phage display peptide biopanning, 3D-modelling, and ELISA. The IgG1 format of the antibody could enhance phagocytosis of C. acnes DMST 14916 by THP-1 human monocytes. Our results suggest that the antibody-dependent phagocytosis process is mediated by the caveolae membrane system and involves the induction of IL-1ß. This is the first report on the study of a human antibody against CAMP1 of C. acnes phylotype II, of which a potential use as therapeutic antibody against virulence C. acnes infection is postulated.
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Inmunoglobulina G , Macrófagos , Fagocitosis , Humanos , Macrófagos/inmunología , Macrófagos/microbiología , Inmunoglobulina G/inmunología , Interleucina-1beta/metabolismo , Interleucina-1beta/inmunología , Células THP-1 , Factores de Virulencia/inmunología , Anticuerpos Antibacterianos/inmunología , Monocitos/inmunología , Monocitos/microbiología , Anticuerpos de Cadena Única/inmunología , Proteínas Bacterianas/inmunología , Proteínas Bacterianas/genética , Propionibacteriaceae/inmunologíaRESUMEN
OBJECTIVES: Canakinumab, a human monoclonal antibody targeted at interleukin-1 beta, has demonstrated safety and efficacy in preventing familial Mediterranean fever (FMF) attacks among individuals with colchicine-resistant (crFMF). The manufacturer orders prescribe monthly subcutaneous injections. However, a subset of our patients is treated with an "canakinumab on demand " (COD) strategy, with wider intervals between drug administrations. Therefore, we aimed to compare disease activity and drug safety between COD and "canakinumab fixed frequency" (CFF) policies. METHODS: This retrospective study collected data from three Israeli paediatric rheumatology centres, of children with crFMF who were treated with canakinumab. Epidemiological and clinical parameters, cumulative drug dosages, and adverse events were compared between children treated by both policies. RESULTS: Twenty-five (49 %) children were treated according to COD policy and 26 according to CFF policy. Demographic parameters and most of the disease features did not differ significantly between the groups. Both groups showed significant reduction in attacks after canakinumab introduction. The median number (interquartile range) of attacks per month did not differ significantly between the COD and CFF groups (0.33 (0.08, 0.58) and 0.13 (0, 0.5), respectively, p = 0.485 (even though, per definition, COD patients presumably had an attack before receiving the second canakinumab dose). The mean monthly dose was lower for the COD than the CFF group (1.13 ± 1.13 vs. 3.16 ± 1.46 mg/kg, p < 0.001). Adverse events were similar between the groups. CONCLUSION: For individuals with crFMF, COD compared to CFF policy can achieve similar efficacy and safety, with a lower accumulated canakinumab dose, rendering it less immunosuppressive and less expensive.