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The dense nerve and thin vascular structure of the corneal tissue provide the refractive function in healthy eyes. Diabetes mellitus causes ocular complications including corneal opacification because of corneal nerve degeneration. Diabetic neurotrophic keratopathy is characterized by reduced corneal sensitivity, delayed corneal wound healing, and nerve degeneration. Neurotization and vascularization inhibit each other in the cornea. Macrophages contribute to the corneal neovascularization. To investigate the role of macrophage in neurotrophic keratopathy, clodronate liposome was subconjunctivally injected into diabetic db/db mice with neurotrophic keratopathy. The clodronate liposome treatment decreased F4/80+ macrophage infiltration into the corneal epithelium, and improved corneal nerve involvement in diabetic db/db mice. Furthermore, we found that interleukin (IL)-1ß and IL-34 mRNA expression was increased in the corneal epithelium of clodronate-treated diabetic db/db mice. These cytokines contribute to the maintenance of nerve tissues via microglia and nerve regeneration; however, their role in corneal nerve involvement remains unknown. Notably, the intraocular injection of recombinant IL-1ß and IL-34 promoted nerve regeneration in the cornea of diabetic db/db mice. These results suggest that clodronate liposome treatment contributes to nerve regeneration during corneal involvement via IL-1ß and IL-34 signaling.
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The complement active product, C3a, and the receptor C3aR comprise an axis that exerts various biological functions, such as protection against infection. C3a is highly expressed in the inflamed skin and blood from patients with psoriasiform dermatitis. However, the role of the C3a/C3aR axis in psoriasiform dermatitis remains unclear because conflicting results using C3-/- mice have been published. In this study, to elucidate the contribution of commensal microbiota in C3-/- and wild-type (WT) mice were subjected to imiquimod-induced psoriasiform dermatitis under different housing conditions. C3-/- mice showed increased epidermal thickness and keratinocyte proliferation markers in the inflamed ear compared to WT mice upon treatment with IMQ. These inflamed phenotypes were observed in both cohoused and separately housed conditions, and antibiotic treatment did not abolish the aggravation of IMQ-induced psoriasiform dermatitis in C3-/- mice. These results suggested that the difference of commensal microbiota is not important for the C3-involved psoriasiform dermatitis. Keratinocyte hyperproliferation is a major feature of the inflamed skin in patients with psoriasiform dermatitis. In vitro experiments showed that C3a and C3aR agonists inhibited keratinocyte proliferation, which was abolished by introduction of a C3aR antagonist. Collectively, these results suggest that the C3a/C3aR axis plays a critical role in psoriasiform dermatitis development by inhibiting keratinocyte proliferation, regardless of the regulation of the commensal microbiota.
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Excessive activation of immune cells by environmental factors, such as infection or individual genetic risk, causes various autoimmune diseases. Streptococcus species are gram-positive bacteria that colonize the nasopharynx, respiratory tract, gastrointestinal tract, genitourinary tract, and skin. Group A Streptococcus (GAS) species cause various symptoms, ranging from mild infections, such as tonsillitis and pharyngitis, to serious infections, such as necrotizing fasciitis and streptococcal toxic shock syndrome. The contribution of GAS infections to several autoimmune diseases, including acute rheumatic fever, vasculitis, and neuropsychiatric disorders, has been studied. In this review, we focus on the association between streptococcal infections and autoimmune diseases, and discuss current research on the mechanisms underlying the initiation and progression of autoimmune diseases.
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Enfermedades Autoinmunes , Faringitis , Fiebre Reumática , Infecciones Estreptocócicas , Humanos , Infecciones Estreptocócicas/microbiología , Streptococcus pyogenes , Enfermedades Autoinmunes/complicacionesRESUMEN
Behçet disease (BD) and relapsing polychondritis (RP) are chronic multisystem disorders characterized by recurrent flare-ups of tissue inflammation. Major clinical manifestations of BD are oral aphthae, genital aphthous ulcers, skin lesions, arthritis, and uveitis. Patients with BD may develop rare but serious neural, intestinal, and vascular complications, with high relapse rates. Meanwhile, RP is characterized by the inflammation of the cartilaginous tissues of the ears, nose, peripheral joints, and tracheobronchial tree. Additionally, it affects the proteoglycan-rich structures in the eyes, inner ear, heart, blood vessels, and kidneys. The mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome is a common characteristic of BD and RP. The immunopathology of these two diseases may be closely related. It is established that the genetic predisposition to BD is related to the human leukocyte antigen (HLA)-B51 gene. Skin histopathology demonstrates the overactivation of innate immunity, such as neutrophilic dermatitis/panniculitis, in patients with BD. Monocytes and neutrophils frequently infiltrate cartilaginous tissues of patients with RP. Somatic mutations in UBA1, which encodes a ubiquitylation-related enzyme, cause vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS) with severe systemic inflammation and activation of myeloid cells. VEXAS prompts auricular and/or nasal chondritis, with neutrophilic infiltration around the cartilage in 52-60% of patients. Thus, innate immune cells may play an important role in the initiation of inflammatory processes underlying both diseases. This review summarizes the recent advances in our understanding of the innate cell-mediated immunopathology of BD and RP, with a focus on the common and distinct features of these mechanisms.
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Celastrol, a bioactive molecule extracted from the Tripterygium wilfordii plant, has been shown to exhibit anti-inflammatory properties. However, its mechanism of action has not been fully elucidated. Here, we show that celastrol suppresses humoral immune responses and autoimmunity by disabling a protein complex consisting of copper metabolism MURR1 domain-containing (COMMD) 3 and COMMD8 (COMMD3/8 complex), a signaling adaptor for chemoattractant receptors. Having demonstrated the involvement of the COMMD3/8 complex in a mouse model of rheumatoid arthritis, we identified celastrol as a compound that covalently bound to and dissociated the COMMD3/8 complex. Celastrol inhibited B cell migration, reduced antibody responses, and blocked arthritis progression, recapitulating deficiency of the COMMD3/8 complex. These effects of celastrol were abolished in mice expressing a celastrol-resistant mutant of the COMMD3/8 complex. These findings establish that celastrol exerts immunosuppressive activity by targeting the COMMD3/8 complex. Our study suggests that the COMMD3/8 complex is a potentially druggable target in autoimmune diseases and points to celastrol as a lead pharmacologic candidate in this capacity.
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Enfermedades Autoinmunes , Inmunidad Humoral , Ratones , Animales , Autoinmunidad , Triterpenos PentacíclicosRESUMEN
Rheumatoid arthritis (RA) is an autoimmune disease that commonly causes inflammation and bone destruction in multiple joints. Inflammatory cytokines, such as IL-6 and TNF-α, play important roles in RA development and pathogenesis. Biological therapies targeting these cytokines have revolutionized RA therapy. However, approximately 50% of the patients are non-responders to these therapies. Therefore, there is an ongoing need to identify new therapeutic targets and therapies for patients with RA. In this review, we focus on the pathogenic roles of chemokines and their G-protein-coupled receptors (GPCRs) in RA. Inflamed tissues in RA, such as the synovium, highly express various chemokines to promote leukocyte migration, tightly controlled by chemokine ligand-receptor interactions. Because the inhibition of these signaling pathways results in inflammatory response regulation, chemokines and their receptors could be promising targets for RA therapy. The blockade of various chemokines and/or their receptors has yielded prospective results in preclinical trials using animal models of inflammatory arthritis. However, some of these strategies have failed in clinical trials. Nonetheless, some blockades showed promising results in early-phase clinical trials, suggesting that chemokine ligand-receptor interactions remain a promising therapeutic target for RA and other autoimmune diseases.
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Artritis Reumatoide , Enfermedades Autoinmunes , Animales , Receptores de Quimiocina , Ligandos , Estudios Prospectivos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/etiología , Quimiocinas , CitocinasRESUMEN
Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by cognitive dysfunction and neuropsychiatric symptoms, is the most prevalent form of dementia among the elderly. Amyloid aggregation, tau hyperphosphorylation, and neural cell loss are the main pathological features. Various hypotheses have been proposed to explain the development of AD. Some therapeutic agents have shown clinical benefits in patients with AD; however, many of these agents have failed. The degree of neural cell loss is associated with the severity of AD. Adult neurogenesis, which governs cognitive and emotional behaviors, occurs in the hippocampus, and some research groups have reported that neural cell transplantation into the hippocampus improves cognitive dysfunction in AD model mice. Based on these clinical findings, stem cell therapy for patients with AD has recently attracted attention. This review provides past and present therapeutic strategies for the management and treatment of AD.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Ratones , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedades Neurodegenerativas/complicaciones , Enfermedades Neurodegenerativas/patología , Neuronas/patología , Neurogénesis , Trasplante de Células MadreRESUMEN
Periodontal tissue supports teeth in the alveolar bone socket via fibrous attachment of the periodontal ligament (PDL). The PDL contains periodontal fibroblasts and stem/progenitor cells, collectively known as PDL cells (PDLCs), on top of osteoblasts and cementoblasts on the surface of alveolar bone and cementum, respectively. However, the characteristics and lineage hierarchy of each cell type remain poorly defined. This study identified periodontal ligament associated protein-1 (Plap-1) as a PDL-specific extracellular matrix protein. We generated knock-in mice expressing CreERT2 and GFP specifically in Plap-1-positive PDLCs. Genetic lineage tracing confirmed the long-standing hypothesis that PDLCs differentiate into osteoblasts and cementoblasts. A PDL single-cell atlas defined cementoblasts and osteoblasts as Plap-1-Ibsp+Sparcl1+ and Plap-1-Ibsp+Col11a2+, respectively. Other populations, such as Nes+ mural cells, S100B+ Schwann cells, and other non-stromal cells, were also identified. RNA velocity analysis suggested that a Plap-1highLy6a+ cell population was the source of PDLCs. Lineage tracing of Plap-1+ PDLCs during periodontal injury showed periodontal tissue regeneration by PDLCs. Our study defines diverse cell populations in PDL and clarifies the role of PDLCs in periodontal tissue homeostasis and repair.
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Ligamento Periodontal , Transcriptoma , Animales , Proteínas de Unión al Calcio/metabolismo , Diferenciación Celular/genética , Proteínas de la Matriz Extracelular/metabolismo , Ratones , Osteoblastos , ARN/metabolismoRESUMEN
The immune checkpoint molecules such as PD-L1 and PD-L2 have a substantial contribution to cancer immunotherapy including breast cancer. Microarray expression profiling identified several molecular subtypes, namely luminal-type (with a good-prognosis), HER2-type (with an intermediate-prognosis), and triple-negative breast cancer (TNBC)-type (with a poor-prognosis). We found that PD-L1 and PD-L2 mRNA expressions were highly expressed in TNBC-type cell lines (HCC1937, MDA-MB-231), moderately expressed in HER2-type cell line (SK-BR-3), and poorly expressed in luminal-type cell lines (MDA-MB-361, MCF7). The PD-L1 and PD-L2 expression in SK-BR-3 cells, but not those in HCC1937 and MDA-MB-231 cells, decreased by nicotine stimulation in a dose-dependent manner. In addition, nicotine treatment decreased the phosphorylation of Akt in SK-BR-3 cells, but not in other cell lines. These results show that nicotine regulates the expression of immune checkpoint molecules, PD-L1 and PD-L2, via inhibition of Akt phosphorylation. This findings may provide the new therapeutic strategies for the treatment of breast cancer.
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Antígeno B7-H1/genética , Neoplasias de la Mama/genética , Nicotina/farmacología , Proteína 2 Ligando de Muerte Celular Programada 1/genética , Receptor ErbB-2/genética , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
C1q/TNF-related proteins (CTRP) including CTRP3 are a group of secreted proteins which have a complement C1q-like domain in common, and play versatile roles in lipid metabolism, inflammation, tumor metastasis and bone metabolism. Previously, we showed that the expression of C1qtnf3, encoding CTRP3, is highly augmented in joints of autoimmune arthritis models and CTRP3-deficiency exacerbates collagen-induced arthritis in mice. However, the mechanisms how CTRP3-deficiency exacerbates arthritis still remain to be elucidated. In this study, we showed that CTRP3 was highly expressed in Th17 cell, a key player for the development of autoimmune diseases, and Th17 cell differentiation was augmented in C1qtnf3-/- mice. Th17 cell differentiation, but not Th1 cell differentiation, was suppressed by CTRP3 and this suppression was abolished by the treatment with a receptor antagonist against AdipoR2, but not AdipoR1, associated with suppression of Rorc and Stat3 expression. Furthermore, AdipoR1 and AdipoR2 agonist, AdipoRon suppressed Th17 cell differentiation via AdipoR2, but not AdipoR1. The development of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis was enhanced in C1qtnf3-/- mice associated with increase of Th17 cell population. CTRP3 inhibited MOG-induced IL-17 production from T cells by affecting both T cells and dendritic cells. These results show that CTRP3 is an endogenous regulator of Th17 differentiation, suggesting that the CTRP3-AdipoR2 axis is a good target for the treatment of Th17 cell-mediated diseases.
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Adipoquinas/inmunología , Diferenciación Celular/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Receptores de Adiponectina/inmunología , Células Th17/inmunología , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/inmunologíaRESUMEN
Elderly patients with dementia suffer from cognitive dysfunctions and neuropsychiatric symptoms (NPS) such as anxiety and depression. Alzheimer's disease (AD) is a form of age-related dementia, and loss of cholinergic neurons is intimately associated with development of AD symptoms. We and others have reported that neural cell transplantation ameliorated cognitive dysfunction in AD model mice. It remains largely unclear whether neural cell transplantation ameliorates the NPS of AD. It would be interesting to determine whether NPS correlates with cognitive dysfunctions before and after neural cell transplantation in AD model mice. Based on the revalidation of our previous data from a Morris water maze test, we found that neural cell transplantation improved anxiety and depression significantly and marginally affected locomotion activity in AD mice. A correlation analysis revealed that the spatial learning function of AD mice was correlated with their NPS scores both before and after cell transplantation in a similar manner. In contrast, in the mice subjected to cell transplantation, spatial reference memory function was not correlated with NPS scores. These results suggested the neural cell transplantation in the AD model mice significantly improved NPS to the same degree as cognitive dysfunctions, possibly via distinct mechanisms, such as the cholinergic and GABAergic systems.
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Enfermedad de Alzheimer/fisiopatología , Ansiedad/fisiopatología , Disfunción Cognitiva/fisiopatología , Depresión/fisiopatología , Locomoción , Células-Madre Neurales/trasplante , Aprendizaje Espacial , Animales , Modelos Animales de Enfermedad , Ratones , Pruebas NeuropsicológicasRESUMEN
Alzheimer's disease (AD) is a prevalent neurological disorder affecting memory function in elderly persons. Indeed, AD exhibits abnormality in cognitive behaviors and higher susceptibility to neuropsychiatric symptoms (NPS). Various factors including aging, sex difference and NPS severity, are implicated during in development of AD. In this study, we evaluated behavioral abnormalities of AD model, PDAPP transgenic mice at young age using the Morris Water Maze test, which was established to assess hippocampal-dependent learning and memory. We found that female AD model mice exhibited spatial learning dysfunction and highly susceptible to NPS such as anxiety and depression, whereas spatial reference memory function was comparable in female PDAPP Tg mice to female wild type (WT) mice. Spatial learning function was comparable in male AD model mice to male WT mice. Multiple regression analysis showed that spatial learning dysfunction was associated with NPS severity such as anxiety and depression. Furthermore, the analysis showed that spatial reference memory function was associated with status of depression, but not anxiety. Thus, these results suggest female dominance of spatial learning dysfunction in the AD model mice accompanying increased NPS severity. The understandings of AD model may be useful for the development of therapeutic agents and methods in human AD.
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Enfermedad de Alzheimer/fisiopatología , Ansiedad/fisiopatología , Depresión/fisiopatología , Aprendizaje Espacial , Memoria Espacial , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Transgénicos , Prueba del Laberinto Acuático de Morris , Factores SexualesRESUMEN
TARM1 is a member of the leukocyte immunoglobulin-like receptor family and stimulates macrophages and neutrophils in vitro by associating with FcRγ. However, the function of this molecule in the regulation of the immune system is unclear. Here, we show that Tarm1 expression is elevated in the joints of rheumatoid arthritis mouse models, and the development of collagen-induced arthritis (CIA) is suppressed in Tarm1-/- mice. T cell priming against type 2 collagen is suppressed in Tarm1-/- mice and antigen-presenting ability of GM-CSF-induced dendritic cells (GM-DCs) from Tarm1-/- mouse bone marrow cells is impaired. We show that type 2 collagen is a functional ligand for TARM1 on GM-DCs and promotes DC maturation. Furthermore, soluble TARM1-Fc and TARM1-Flag inhibit DC maturation and administration of TARM1-Fc blocks the progression of CIA in mice. These results indicate that TARM1 is an important stimulating factor of dendritic cell maturation and could be a good target for the treatment of autoimmune diseases.
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Artritis Experimental/metabolismo , Artritis Experimental/patología , Colágeno/metabolismo , Células Dendríticas/patología , Receptores Inmunológicos/metabolismo , Animales , Presentación de Antígeno , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Proteínas Fluorescentes Verdes/metabolismo , Inmunización , Ligandos , Ratones Endogámicos C57BL , Receptores Inmunológicos/deficienciaRESUMEN
Reelin is a large glycoprotein which regulates central nervous system (CNS) development. Dysfunctions of Reelin were reported on certain neuropsychiatric diseases. We examined involvement of Reelin pathway in functional recovery of hemiplegic mice after neural transplantation. Reelin was expressed 1â¯day after cryogenic injury of right motor cortex. We transplanted neural stem/progenitor cells (NSPCs) from wild-type mice into ipsilateral striatum of hemiplegic mice. The grafts migrated from the striatum and reached the injured cortex 14â¯days after transplantation. The transplantation significantly improved their motor functions (Pâ¯<â¯.05). The NSPCs migrating toward the cortex expressed Reelin receptors, Apoer and Vldlr, and phosphorylated Disabled1 (Dab1), a downstream signaling molecule of Reelin. The grafts expressed Ncadherin and active form of Integrin ß1, both of which were known to become active with Reelin stimulation. At day 28, the grafts expressed Ctip2, Crim1, Foxp2, and Fezf2, all of which were forebrain motoneuron associated markers, and Nfm and Synapsin1 on the damaged cortex. We then transplanted NSPCs of yotari mice (yot/yot genotype) having nonfunctional Dab1 by a mutation of its gene. Majority of the grafts from yotari mice (>80%) did not migrate and thus remained at the striatum. The grafts did not express the forebrain motoneuron associated markers nor the cell adhesion molecules including Ncadherin and active Integrin ß1. Reelin pathway was involved in graft migration by regulating certain adhesion molecules and in their differentiation to functional motoneurons accompanying synapse formation. We suggested involvement of Reelin pathway for neural regeneration and functional recovery of hemiplegic mice in adulthood after neural transplantation.
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Moléculas de Adhesión Celular Neuronal/metabolismo , Diferenciación Celular/fisiología , Proteínas de la Matriz Extracelular/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Células-Madre Neurales/trasplante , Recuperación de la Función/fisiología , Serina Endopeptidasas/metabolismo , Animales , Movimiento Celular/fisiología , Hemiplejía/fisiopatología , Ratones , Corteza Motora/metabolismo , Neuronas Motoras/citología , Neuronas Motoras/metabolismo , Células-Madre Neurales/citología , Proteína Reelina , Trasplante de Células MadreRESUMEN
NLRP3 inflammasome plays a critical spatiotemporal role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). This study reports a mechanistic insight into noncanonical NLRP3 inflammasome activation in microglia for the effector stage of EAE. Microglia-specific deficiency of ASC (apoptosis-associated speck-like protein containing a C-terminal caspase-activation and recruitment [CARD] domain) attenuated T cell expansion and neutrophil recruitment during EAE pathogenesis. Mechanistically, TLR stimulation led to IRAKM-caspase-8-ASC complex formation, resulting in the activation of caspase-8 and IL-1ß release in microglia. Noncanonical inflammasome-derived IL-1ß produced by microglia in the CNS helped to expand the microglia population in an autocrine manner and amplified the production of inflammatory cytokines/chemokines. Furthermore, active caspase-8 was markedly increased in the microglia in the brain tissue from patients with multiple sclerosis. Taken together, our study suggests that microglia-derived IL-1ß via noncanonical caspase-8-dependent inflammasome is necessary for microglia to exert their pathogenic role during CNS inflammation.
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Caspasa 8/metabolismo , Encefalomielitis Autoinmune Experimental/enzimología , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Microglía/metabolismo , Esclerosis Múltiple/enzimología , Transducción de Señal , Animales , Caspasa 8/genética , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/patología , Femenino , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Quinasas Asociadas a Receptores de Interleucina-1/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Noqueados , Microglía/patología , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismoRESUMEN
Relapsing polychondritis (RP) is an inflammatory disease of unknown causes, characterized by recurrent inflammation in cartilaginous tissues of the whole body. Recently, researchers have reported that, in mouse experiments, altered gut microbe-dependent T cell differentiation occurred in gut associated lymphoid tissues. Here, we investigated whether gut microbe alteration existed, and if so, the alteration affected peripheral T cell differentiation in patients with RP. In an analysis of gut microbiota, we found increased annotated species numbers in RP patients compared with normal individuals. In the RP gut microbiota, we observed several predominant species, namely Veillonella parvula, Bacteroides eggerthii, Bacteroides fragilis, Ruminococcus bromii, and Eubacterium dolichum, all species of which were reported to associate with propionate production in human intestine. Propionate is a short-chain fatty acid and is suggested to associate with interleukin (IL)10-producing regulatory T (Treg) cell differentiation in gut associated lymphoid tissues. IL10 gene expressions were moderately higher in freshly isolated peripheral blood mononuclear cells (PBMC) of RP patients than those of normal individuals. Six hours after the initiation of the cell culture, regardless of the presence and absence of mitogen stimulation, IL10 gene expressions were significantly lower in RP patients than those in normal individuals. It is well known that PBMC of patients with autoimmune and inflammatory diseases show hyporesponsiveness to mitogen stimulation. We suggest that, in RP patients, continuous stimulation of intestinal T cells by excessive propionate leads to the spontaneous IL10 production and a subsequent refractory period of T cells in patients with RP. The hyporesponsiveness of Treg cells upon activation may associate with inflammatory cytokine production of PBMC and subsequently relate to chondritis in RP patients.
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Microbioma Gastrointestinal , Interleucina-10/metabolismo , Policondritis Recurrente/microbiología , Propionatos/metabolismo , Linfocitos T/metabolismo , Diferenciación Celular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Policondritis Recurrente/inmunología , Linfocitos T/patologíaRESUMEN
IL-36α (gene symbol Il1f6), a member of the IL-36 family, is closely associated with inflammatory diseases, including colitis and psoriasis. In this study, we found that Il1f6-/- mice developed milder psoriasiform dermatitis upon treatment with imiquimod, a ligand for TLR ligand 7 (TLR7) and TLR8, whereas Il1f6-/- mice showed similar susceptibility to dextran sodium sulfate-induced colitis to wild-type mice. These effects were observed in both cohoused and separately housed conditions, and antibiotic treatment did not cancel the resistance of Il1f6-/- mice to imiquimod-induced dermatitis. Bone marrow (BM) cell transfer revealed that IL-36α expression in skin-resident cells is important for the pathogenesis of dermatitis in these mice. Following stimulation with IL-36α, the expression of Il1f6 and Il1f9 (IL-36γ), but not Il1f8 (IL-36ß), was enhanced in murine BM-derived Langerhans cells (BMLCs) and murine primary keratinocytes but not in fibroblasts from mice. Upon stimulation with agonistic ligands of TLRs and C-type lectin receptors (CLRs), Il1f6 expression was induced in BMLCs and BM-derived dendritic cells. Furthermore, IL-36α stimulation resulted in significantly increased gene expression of psoriasis-associated Th17-related cytokines and chemokines such as IL-1α, IL-1ß, IL-23, CXCL1, and CXCL2 in BMLCs and fibroblasts, and IL-1α, IL-1ß, IL-17C, and CXCL2 in keratinocytes. Collectively, these results suggest that TLR/CLR signaling-induced IL-36α plays an important role for the development of psoriasiform dermatitis by enhancing Th17-related cytokine/chemokine production in skin-resident cells via a local autoamplification loop.
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Adyuvantes Inmunológicos/toxicidad , Quimiocinas/biosíntesis , Colitis/patología , Imiquimod/toxicidad , Interleucina-1/metabolismo , Queratinocitos/metabolismo , Psoriasis/patología , Piel/patología , Células Th17/inmunología , Animales , Células de la Médula Ósea/citología , Trasplante de Médula Ósea , Células Cultivadas , Colitis/inducido químicamente , Células Dendríticas/metabolismo , Sulfato de Dextran/toxicidad , Fibroblastos/metabolismo , Interleucina-1/genética , Células de Langerhans/metabolismo , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Psoriasis/tratamiento farmacológico , Psoriasis/genética , Piel/citología , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 8/metabolismoRESUMEN
Ulcerative colitis (UC) is an inflammatory disease of the colon. IL1R2, which encodes IL-1 receptor type 2 (IL-1R2), was reported as a risk gene for UC. To elucidate the roles of IL-1R2 in the development of colitis, we examined the development of dextran sodium sulfate-induced colitis, a mouse model for UC using Il1r2-/- mice. We found the severity score of colitis was milder in Il1r2-/- mice compared with wild-type (WT) mice when they were housed separately, however the severity score was similar when they were housed in a cage. In the separate housing condition, relative contents of Actinobacteria and Bacilli in feces of Il1r2-/- mice were lower than that of WT mice. Furthermore, IL-1ß induced the expression of antimicrobial peptides (AMPs) from colon. Thus, we show that IL-1R2 is harmful for the development of colitis, because IL-1R2 promotes the growth of proinflammatory intestinal microbiota by suppressing IL-1ß-induced AMP production.
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Péptidos Catiónicos Antimicrobianos/inmunología , Colitis/inmunología , Microbioma Gastrointestinal/inmunología , Receptores de Interleucina-1/inmunología , Animales , Colitis/inducido químicamente , Colitis/patología , Sulfato de Dextran , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Interleucina-1/genéticaRESUMEN
The complement system is important for the host defence against infection as well as for the development of inflammatory diseases. Here we show that C1q/TNF-related protein 6 (CTRP6; gene symbol C1qtnf6) expression is elevated in mouse rheumatoid arthritis (RA) models. C1qtnf6(-/-) mice are highly susceptible to induced arthritis due to enhanced complement activation, whereas C1qtnf6-transgenic mice are refractory. The Arthus reaction and the development of experimental autoimmune encephalomyelitis are also enhanced in C1qtnf6(-/-) mice and C1qtnf6(-/-) embryos are semi-lethal. We find that CTRP6 specifically suppresses the alternative pathway of the complement system by competing with factor B for C3(H2O) binding. Furthermore, treatment of arthritis-induced mice with intra-articular injection of recombinant human CTRP6 cures the arthritis. CTRP6 is expressed in human synoviocytes, and CTRP6 levels are increased in RA patients. These results indicate that CTRP6 is an endogenous complement regulator and could be used for the treatment of complement-mediated diseases.
Asunto(s)
Adipoquinas/inmunología , Artritis Experimental/inmunología , Artritis Reumatoide/inmunología , Vía Alternativa del Complemento/inmunología , Adipoquinas/genética , Adulto , Animales , Artritis Experimental/genética , Artritis Experimental/patología , Artritis Reumatoide/genética , Artritis Reumatoide/patología , Reacción de Arthus/genética , Reacción de Arthus/inmunología , Reacción de Arthus/metabolismo , Western Blotting , Colágeno/inmunología , Colágeno/metabolismo , Convertasas de Complemento C3-C5/inmunología , Complemento C3a/inmunología , Complemento C5a/inmunología , Vía Alternativa del Complemento/genética , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Citometría de Flujo , Humanos , Inmunoprecipitación , Macrófagos/inmunología , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Membrana Sinovial/citología , Membrana Sinovial/metabolismoRESUMEN
IL-1R antagonist-deficient (Il1rn(-/-)) mice develop autoimmune arthritis in which IL-17A plays a crucial role. Although many studies have shown that Th17 cell differentiation is dependent on TGF-ß and IL-6, we found that Th17 cells developed normally in Il1rn(-/-)Il6(-/-) mice in vivo. Then, we analyzed the mechanisms of Th17 cell differentiation in Il1rn(-/-)Il6(-/-) mice. We found that IL-21 production was increased in the lymph nodes of Il1rn(-/-) mice, naive Il6(-/-) CD4(+) T cells differentiated into Th17 cells when cultured with TGF-ß and IL-21, and the differentiation was greatly enhanced when IL-1 was added to the culture. Th17 cell differentiation was not induced by either TGF-ß or IL-1 alone or in combination. IL-21 induced IL-1R expression in naive CD4(+) T cells, and IL-1 inhibited TGF-ß-induced Foxp3 expression, resulting in the promotion of Th17 cell differentiation. Furthermore, IL-1 augmented the expression of Th17 cell-specific transcription factors such as Nfkbiz and Batf. These results indicate that excess IL-1 signaling can overcome the requirement of IL-6 in the differentiation of Th17 cells by suppressing Foxp3 expression and inducing Th17 cell-specific transcription factors.