RESUMEN
The diverse biological activity of interleukin-6 (IL-6) contributes to the maintenance of homeostasis. Emergent infection or tissue injury induces rapid production of IL-6 and activates host defense through augmentation of acute-phase proteins and immune responses. However, excessive IL-6 production and uncontrolled IL-6 receptor signaling are critical to pathogenesis. Over the years, therapeutic agents targeting IL-6 signaling, such as tocilizumab, a humanized anti-IL-6 receptor antibody, have shown remarkable efficacy for rheumatoid arthritis, Castleman disease, and juvenile idiopathic arthritis, and their efficacy in other diseases is continually being reported. Emerging evidence has demonstrated the benefit of tocilizumab for several types of acute inflammatory diseases, including cytokine storms induced by chimeric antigen receptor T cell therapy and coronavirus disease 2019 (COVID-19). Here, we refocus attention on the biology of IL-6 and summarize the distinct pathological roles of IL-6 signaling in several acute and chronic inflammatory diseases.
Asunto(s)
Artritis Reumatoide , COVID-19 , Animales , Artritis Reumatoide/terapia , COVID-19/terapia , Humanos , Inmunoterapia Adoptiva , Interleucina-6/metabolismo , Transducción de SeñalRESUMEN
Inflammation can trigger lasting phenotypes in immune and non-immune cells. Whether and how human infections and associated inflammation can form innate immune memory in hematopoietic stem and progenitor cells (HSPC) has remained unclear. We found that circulating HSPC, enriched from peripheral blood, captured the diversity of bone marrow HSPC, enabling investigation of their epigenomic reprogramming following coronavirus disease 2019 (COVID-19). Alterations in innate immune phenotypes and epigenetic programs of HSPC persisted for months to 1 year following severe COVID-19 and were associated with distinct transcription factor (TF) activities, altered regulation of inflammatory programs, and durable increases in myelopoiesis. HSPC epigenomic alterations were conveyed, through differentiation, to progeny innate immune cells. Early activity of IL-6 contributed to these persistent phenotypes in human COVID-19 and a mouse coronavirus infection model. Epigenetic reprogramming of HSPC may underlie altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors.
Asunto(s)
COVID-19 , Memoria Epigenética , Síndrome Post Agudo de COVID-19 , Animales , Humanos , Ratones , Diferenciación Celular , COVID-19/inmunología , Modelos Animales de Enfermedad , Células Madre Hematopoyéticas , Inflamación/genética , Inmunidad Entrenada , Monocitos/inmunología , Síndrome Post Agudo de COVID-19/genética , Síndrome Post Agudo de COVID-19/inmunología , Síndrome Post Agudo de COVID-19/patologíaRESUMEN
Blood and lymphatic vessels form a versatile transport network and provide inductive signals to regulate tissue-specific functions. Blood vessels in bone regulate osteogenesis and hematopoiesis, but current dogma suggests that bone lacks lymphatic vessels. Here, by combining high-resolution light-sheet imaging and cell-specific mouse genetics, we demonstrate presence of lymphatic vessels in mouse and human bones. We find that lymphatic vessels in bone expand during genotoxic stress. VEGF-C/VEGFR-3 signaling and genotoxic stress-induced IL6 drive lymphangiogenesis in bones. During lymphangiogenesis, secretion of CXCL12 from proliferating lymphatic endothelial cells is critical for hematopoietic and bone regeneration. Moreover, lymphangiocrine CXCL12 triggers expansion of mature Myh11+ CXCR4+ pericytes, which differentiate into bone cells and contribute to bone and hematopoietic regeneration. In aged animals, such expansion of lymphatic vessels and Myh11-positive cells in response to genotoxic stress is impaired. These data suggest lymphangiogenesis as a therapeutic avenue to stimulate hematopoietic and bone regeneration.
Asunto(s)
Regeneración Ósea , Vasos Linfáticos , Anciano , Animales , Humanos , Ratones , Células Endoteliales , LinfangiogénesisRESUMEN
Acute psychological stress has long been known to decrease host fitness to inflammation in a wide variety of diseases, but how this occurs is incompletely understood. Using mouse models, we show that interleukin-6 (IL-6) is the dominant cytokine inducible upon acute stress alone. Stress-inducible IL-6 is produced from brown adipocytes in a beta-3-adrenergic-receptor-dependent fashion. During stress, endocrine IL-6 is the required instructive signal for mediating hyperglycemia through hepatic gluconeogenesis, which is necessary for anticipating and fueling "fight or flight" responses. This adaptation comes at the cost of enhancing mortality to a subsequent inflammatory challenge. These findings provide a mechanistic understanding of the ontogeny and adaptive purpose of IL-6 as a bona fide stress hormone coordinating systemic immunometabolic reprogramming. This brain-brown fat-liver axis might provide new insights into brown adipose tissue as a stress-responsive endocrine organ and mechanistic insight into targeting this axis in the treatment of inflammatory and neuropsychiatric diseases.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Interleucina-6/metabolismo , Estrés Psicológico , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Trasplante de Médula Ósea , Encéfalo/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Gluconeogénesis , Hiperglucemia/metabolismo , Hiperglucemia/patología , Interleucina-6/sangre , Interleucina-6/genética , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Adrenérgicos beta 3/metabolismo , Receptores de Interleucina-6/metabolismo , Proteína Desacopladora 1/deficiencia , Proteína Desacopladora 1/genéticaRESUMEN
Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/inmunología , Neumonía Viral/inmunología , Virus ARN/inmunología , Animales , COVID-19 , Células Cultivadas , Quimiocinas/genética , Quimiocinas/inmunología , Infecciones por Coronavirus/genética , Modelos Animales de Enfermedad , Interacciones Huésped-Patógeno , Humanos , Inmunidad Innata , Inflamación/virología , Interferones/genética , Interferones/inmunología , Pandemias , Neumonía Viral/genética , Virus ARN/clasificación , SARS-CoV-2 , Transcripción GenéticaRESUMEN
Immune cell trafficking constitutes a fundamental component of immunological response to tissue injury, but the contribution of intrinsic RNA nucleotide modifications to this response remains elusive. We report that RNA editor ADAR2 exerts a tissue- and stress-specific regulation of endothelial responses to interleukin-6 (IL-6), which tightly controls leukocyte trafficking in IL-6-inflamed and ischemic tissues. Genetic ablation of ADAR2 from vascular endothelial cells diminished myeloid cell rolling and adhesion on vascular walls and reduced immune cell infiltration within ischemic tissues. ADAR2 was required in the endothelium for the expression of the IL-6 receptor subunit, IL-6 signal transducer (IL6ST; gp130), and subsequently, for IL-6 trans-signaling responses. ADAR2-induced adenosine-to-inosine RNA editing suppressed the Drosha-dependent primary microRNA processing, thereby overwriting the default endothelial transcriptional program to safeguard gp130 expression. This work demonstrates a role for ADAR2 epitranscriptional activity as a checkpoint in IL-6 trans-signaling and immune cell trafficking to sites of tissue injury.
Asunto(s)
Interleucina-6 , ARN , Células Endoteliales/metabolismo , Receptor gp130 de Citocinas , Endotelio/metabolismo , Adenosina Desaminasa/genética , Adenosina Desaminasa/metabolismoRESUMEN
The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging XpdTTD/TTD and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored.
Asunto(s)
Envejecimiento/patología , Antibióticos Antineoplásicos/efectos adversos , Péptidos de Penetración Celular/farmacología , Doxorrubicina/efectos adversos , Envejecimiento/efectos de los fármacos , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacología , Apoptosis , Proteínas de Ciclo Celular , Línea Celular , Supervivencia Celular , Senescencia Celular/efectos de los fármacos , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Femenino , Fibroblastos/citología , Factores de Transcripción Forkhead/química , Factores de Transcripción Forkhead/metabolismo , Humanos , Cuerpos de Inclusión/efectos de los fármacos , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/patología , Riñón/efectos de los fármacos , Riñón/fisiología , Hígado/efectos de los fármacos , Hígado/fisiología , Masculino , Ratones , Síndromes de Tricotiodistrofia/tratamiento farmacológico , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Conventional dendritic cells (cDCs), cDC1 and cDC2, act both to initiate immunity and maintain self-tolerance. The tryptophan metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is used by cDCs in maintaining tolerance, but its role in different subsets remains unclear. At homeostasis, only mature CCR7+ cDC1 expressed IDO1 that was dependent on IRF8. Lipopolysaccharide treatment induced maturation and IDO1-dependent tolerogenic activity in isolated immature cDC1, but not isolated cDC2. However, both human and mouse cDC2 could induce IDO1 and acquire tolerogenic function when co-cultured with mature cDC1 through the action of cDC1-derived l-kynurenine. Accordingly, cDC1-specific inactivation of IDO1 in vivo exacerbated disease in experimental autoimmune encephalomyelitis. This study identifies a previously unrecognized metabolic communication in which IDO1-expressing cDC1 cells extend their immunoregulatory capacity to the cDC2 subset through their production of tryptophan metabolite l-kynurenine. This metabolic axis represents a potential therapeutic target in treating autoimmune demyelinating diseases.
Asunto(s)
Indolamina-Pirrol 2,3,-Dioxigenasa , Quinurenina , Animales , Células Dendríticas , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Quinurenina/metabolismo , Ratones , Transducción de Señal , Triptófano/metabolismoRESUMEN
Deregulated inflammation is a critical feature driving the progression of tumors harboring mutations in the liver kinase B1 (LKB1), yet the mechanisms linking LKB1 mutations to deregulated inflammation remain undefined. Here, we identify deregulated signaling by CREB-regulated transcription coactivator 2 (CRTC2) as an epigenetic driver of inflammatory potential downstream of LKB1 loss. We demonstrate that LKB1 mutations sensitize both transformed and non-transformed cells to diverse inflammatory stimuli, promoting heightened cytokine and chemokine production. LKB1 loss triggers elevated CRTC2-CREB signaling downstream of the salt-inducible kinases (SIKs), increasing inflammatory gene expression in LKB1-deficient cells. Mechanistically, CRTC2 cooperates with the histone acetyltransferases CBP/p300 to deposit histone acetylation marks associated with active transcription (i.e., H3K27ac) at inflammatory gene loci, promoting cytokine expression. Together, our data reveal a previously undefined anti-inflammatory program, regulated by LKB1 and reinforced through CRTC2-dependent histone modification signaling, that links metabolic and epigenetic states to cell-intrinsic inflammatory potential.
Asunto(s)
Histonas , Proteínas Serina-Treonina Quinasas , Humanos , Histonas/genética , Histonas/metabolismo , Acetilación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Citocinas/metabolismo , Inflamación/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.
Asunto(s)
Interacciones Huésped-Patógeno , Inmunidad Celular , Neumonía Viral/etiología , Neumonía Viral/metabolismo , Receptor Notch4/metabolismo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Anfirregulina/farmacología , Animales , Biomarcadores , Citocinas/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunohistoquímica , Inmunomodulación/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Virus de la Influenza A/fisiología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Pulmón/virología , Ratones , Ratones Transgénicos , Neumonía Viral/patología , Receptor Notch4/antagonistas & inhibidores , Receptor Notch4/genética , Índice de Severidad de la EnfermedadRESUMEN
Adjuvants are critical for improving the quality and magnitude of adaptive immune responses to vaccination. Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines have shown great efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the mechanism of action of this vaccine platform is not well-characterized. Using influenza virus and SARS-CoV-2 mRNA and protein subunit vaccines, we demonstrated that our LNP formulation has intrinsic adjuvant activity that promotes induction of strong T follicular helper cell, germinal center B cell, long-lived plasma cell, and memory B cell responses that are associated with durable and protective antibodies in mice. Comparative experiments demonstrated that this LNP formulation outperformed a widely used MF59-like adjuvant, AddaVax. The adjuvant activity of the LNP relies on the ionizable lipid component and on IL-6 cytokine induction but not on MyD88- or MAVS-dependent sensing of LNPs. Our study identified LNPs as a versatile adjuvant that enhances the efficacy of traditional and next-generation vaccine platforms.
Asunto(s)
Linfocitos B/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/inmunología , Centro Germinal/inmunología , SARS-CoV-2/fisiología , Linfocitos T Colaboradores-Inductores/inmunología , Vacunas de ARNm/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adyuvantes Inmunológicos , Animales , Células HEK293 , Humanos , Inmunidad Humoral , Interleucina-6/genética , Interleucina-6/metabolismo , Liposomas/administración & dosificación , Ratones , Ratones Endogámicos BALB C , Nanopartículas/administración & dosificación , Subunidades de Proteína/genética , Vacunas de ARNm/genéticaRESUMEN
Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1ß production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.
Asunto(s)
Adenosina Trifosfato/metabolismo , ADN Mitocondrial/biosíntesis , Inflamasomas/efectos de los fármacos , Metformina/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neumonía/prevención & control , Animales , COVID-19/metabolismo , COVID-19/prevención & control , Citocinas/genética , Citocinas/metabolismo , ADN Mitocondrial/metabolismo , Humanos , Inflamasomas/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolisacáridos/toxicidad , Metformina/uso terapéutico , Ratones , Nucleósido-Fosfato Quinasa/metabolismo , Neumonía/metabolismo , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/prevención & control , SARS-CoV-2/patogenicidadRESUMEN
Early prenatal inflammatory conditions are thought to be a risk factor for different neurodevelopmental disorders. Maternal interleukin-6 (IL-6) elevation during pregnancy causes abnormal behavior in offspring, but whether these defects result from altered synaptic developmental trajectories remains unclear. Here we showed that transient IL-6 elevation via injection into pregnant mice or developing embryos enhanced glutamatergic synapses and led to overall brain hyperconnectivity in offspring into adulthood. IL-6 activated synaptogenesis gene programs in glutamatergic neurons and required the transcription factor STAT3 and expression of the RGS4 gene. The STAT3-RGS4 pathway was also activated in neonatal brains during poly(I:C)-induced maternal immune activation, which mimics viral infection during pregnancy. These findings indicate that IL-6 elevation at early developmental stages is sufficient to exert a long-lasting effect on glutamatergic synaptogenesis and brain connectivity, providing a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders.
Asunto(s)
Hipocampo/metabolismo , Interleucina-6/biosíntesis , Exposición Materna , Neuronas/metabolismo , Efectos Tardíos de la Exposición Prenatal , Sinapsis/metabolismo , Animales , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Femenino , Hipocampo/fisiopatología , Mediadores de Inflamación/metabolismo , Ratones , Embarazo , Transducción de Señal , Transmisión SinápticaRESUMEN
The coronavirus disease 2019 (COVID-19) pandemic poses a current world-wide public health threat. However, little is known about its hallmarks compared to other infectious diseases. Here, we report the single-cell transcriptional landscape of longitudinally collected peripheral blood mononuclear cells (PBMCs) in both COVID-19- and influenza A virus (IAV)-infected patients. We observed increase of plasma cells in both COVID-19 and IAV patients and XIAP associated factor 1 (XAF1)-, tumor necrosis factor (TNF)-, and FAS-induced T cell apoptosis in COVID-19 patients. Further analyses revealed distinct signaling pathways activated in COVID-19 (STAT1 and IRF3) versus IAV (STAT3 and NFκB) patients and substantial differences in the expression of key factors. These factors include relatively increase of interleukin (IL)6R and IL6ST expression in COVID-19 patients but similarly increased IL-6 concentrations compared to IAV patients, supporting the clinical observations of increased proinflammatory cytokines in COVID-19 patients. Thus, we provide the landscape of PBMCs and unveil distinct immune response pathways in COVID-19 and IAV patients.
Asunto(s)
Infecciones por Coronavirus/inmunología , Citocinas/inmunología , Gripe Humana/inmunología , Leucocitos Mononucleares/inmunología , Neumonía Viral/inmunología , Transducción de Señal/inmunología , Betacoronavirus/inmunología , COVID-19 , Humanos , Subtipo H1N1 del Virus de la Influenza A/inmunología , Pandemias , SARS-CoV-2RESUMEN
Interleukin-6 (IL-6) is a pleiotropic cytokine with roles in immunity, tissue regeneration, and metabolism. Rapid production of IL-6 contributes to host defense during infection and tissue injury, but excessive synthesis of IL-6 and dysregulation of IL-6 receptor signaling is involved in disease pathology. Therapeutic agents targeting the IL-6 axis are effective in rheumatoid arthritis, and applications are being extended to other settings of acute and chronic inflammation. Recent studies reveal that selective blockade of different modes of IL-6 receptor signaling has different outcomes on disease pathology, suggesting novel strategies for therapeutic intervention. However, some inflammatory diseases do not seem to respond to IL-6 blockade. Here, we review the current state of IL-6-targeting approaches in the clinic and discuss how to apply the growing understanding of the immunobiology of IL-6 to clinical decisions.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Inflamación/tratamiento farmacológico , Interleucina-6/antagonistas & inhibidores , Terapia Molecular Dirigida , Transducción de Señal/efectos de los fármacos , Animales , Anticuerpos Monoclonales/inmunología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Ensayos Clínicos como Asunto , Receptor gp130 de Citocinas/antagonistas & inhibidores , Receptor gp130 de Citocinas/inmunología , Humanos , Inflamación/inmunología , Interleucina-6/biosíntesis , Interleucina-6/deficiencia , Interleucina-6/inmunología , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/fisiología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Ratones Noqueados , Receptores de Interleucina-6/inmunología , Ribonucleasas/deficiencia , Factor de Transcripción STAT3/fisiología , Proteína 1 Supresora de la Señalización de Citocinas/fisiología , Proteína 3 Supresora de la Señalización de Citocinas/fisiologíaRESUMEN
It is unclear how quiescence is enforced in naive T cells, but activation by foreign antigens and self-antigens is allowed, despite the presence of inhibitory signals. We showed that active transforming growth factor ß (TGF-ß) signaling was present in naive T cells, and T cell receptor (TCR) engagement reduced TGF-ß signaling during T cell activation by downregulating TGF-ß type 1 receptor (TßRI) through activation of caspase recruitment domain-containing protein 11 (CARD11) and nuclear factor κB (NF-κB). TGF-ß prevented TCR-mediated TßRI downregulation, but this was abrogated by interleukin-6 (IL-6). Mitigation of TCR-mediated TßRI downregulation through overexpression of TßRI in naive and activated T cells rendered T cells less responsive and suppressed autoimmunity. Naive T cells in autoimmune patients exhibited reduced TßRI expression and increased TCR-driven proliferation compared to healthy subjects. Thus, TCR-mediated regulation of TßRI-TGF-ß signaling acts as a crucial criterion to determine T cell quiescence and activation.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD/metabolismo , Linfocitos T CD4-Positivos/inmunología , Guanilato Ciclasa/metabolismo , Activación de Linfocitos/inmunología , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Autoinmunidad/inmunología , Proteínas Adaptadoras de Señalización CARD/genética , Línea Celular , Proliferación Celular , Colitis/inmunología , Colitis/patología , Modelos Animales de Enfermedad , Regulación hacia Abajo/inmunología , Guanilato Ciclasa/genética , Células HEK293 , Humanos , Interleucina-6/inmunología , Lupus Eritematoso Sistémico/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta/biosíntesis , Transducción de Señal/inmunología , Factor de Crecimiento Transformador beta1/biosíntesisRESUMEN
Protection against endothelial damage is recognized as a frontline approach to preventing the progression of cytokine release syndrome (CRS). Accumulating evidence has demonstrated that interleukin-6 (IL-6) promotes vascular endothelial damage during CRS, although the molecular mechanisms remain to be fully elucidated. Targeting IL-6 receptor signaling delays CRS progression; however, current options are limited by persistent inhibition of the immune system. Here, we show that endothelial IL-6 trans-signaling promoted vascular damage and inflammatory responses via hypoxia-inducible factor-1α (HIF1α)-induced glycolysis. Using pharmacological inhibitors targeting HIF1α activity or mice with the genetic ablation of gp130 in the endothelium, we found that inhibition of IL-6R (IL-6 receptor)-HIF1α signaling in endothelial cells protected against vascular injury caused by septic damage and provided survival benefit in a mouse model of sepsis. In addition, we developed a short half-life anti-IL-6R antibody (silent anti-IL-6R antibody) and found that it was highly effective at augmenting survival for sepsis and severe burn by strengthening the endothelial glycocalyx and reducing cytokine storm, and vascular leakage. Together, our data advance the role of endothelial IL-6 trans-signaling in the progression of CRS and indicate a potential therapeutic approach for burns and sepsis.
Asunto(s)
Receptor gp130 de Citocinas , Subunidad alfa del Factor 1 Inducible por Hipoxia , Interleucina-6 , Receptores de Interleucina-6 , Sepsis , Animales , Ratones , Receptor gp130 de Citocinas/genética , Síndrome de Liberación de Citoquinas , Células Endoteliales , Receptores de Interleucina-6/genética , Sepsis/tratamiento farmacológico , Subunidad alfa del Factor 1 Inducible por Hipoxia/genéticaRESUMEN
Conventional dendritic cells (cDCs) can integrate multiple stimuli from the environment and provide three separate outputs in terms of antigen presentation, costimulation, and cytokine production; this guides the activation, expansion, and differentiation of distinct functional T helper subsets. Accordingly, the current dogma posits that T helper cell specification requires these three signals in sequence. Data show that T helper 2 (Th2) cell differentiation requires antigen presentation and costimulation from cDCs but does not require polarizing cytokines. In this opinion article, we propose that the 'third signal' driving Th2 cell responses is, in fact, the absence of polarizing cytokines; indeed, the secretion of the latter is actively suppressed in cDCs, concomitant with acquired pro-Th2 functions.
Asunto(s)
Citocinas , Células Th2 , Humanos , Linfocitos T Colaboradores-Inductores , Diferenciación Celular , Células TH1RESUMEN
Fibroblasts are major contributors to and regulators of inflammation and dominant producers of interleukin-6 (IL-6) in inflammatory diseases like rheumatoid arthritis. Yet, compared to leukocytes, the regulation of inflammatory pathways in fibroblasts is largely unknown. Here, we report that analyses of genes coordinately upregulated with IL-6 pointed to STAT4 and leukemia inhibitory factor (LIF) as potentially linked. Gene silencing revealed that STAT4 was required for IL-6 transcription. STAT4 was recruited to the IL-6 promoter after fibroblast activation, and LIF receptor (LIFR) and STAT4 formed a molecular complex that, together with JAK1 and TYK2 kinases, controlled STAT4 activation. Importantly, a positive feedback loop involving autocrine LIF, LIFR, and STAT4 drove sustained IL-6 transcription. Besides IL-6, this autorine loop also drove the production of other key inflammatory factors including IL-8, granulocyte-colony stimulating factor (G-CSF), IL-33, IL-11, IL-1α, and IL-1ß. These findings define the transcriptional regulation of fibroblast-mediated inflammation as distinct from leukocytes.
Asunto(s)
Comunicación Autocrina/inmunología , Fibroblastos/inmunología , Regulación de la Expresión Génica/inmunología , Factor Inhibidor de Leucemia/inmunología , Receptores OSM-LIF/inmunología , Artritis Reumatoide/inmunología , Células Cultivadas , Citocinas/biosíntesis , Perfilación de la Expresión Génica , Humanos , Inflamación/inmunología , Interleucina-6/inmunología , Factor de Transcripción STAT4/inmunología , Membrana Sinovial/inmunología , TranscriptomaRESUMEN
Various cytokines have been implicated in cancer cachexia. One such cytokine is IL-6, deemed as a key cachectic factor in mice inoculated with colon carcinoma 26 (C26) cells, a widely used cancer cachexia model. Here we tested the causal role of IL-6 in cancer cachexia by knocking out the IL-6 gene in C26 cells. We found that the growth of IL-6 KO tumors was dramatically delayed. More strikingly, while IL-6 KO tumors eventually reached the similar size as wild-type tumors, cachexia still took place, despite no elevation in circulating IL-6. In addition, the knockout of leukemia inhibitory factor (LIF), another IL-6 family cytokine proposed as a cachectic factor in the model, also affected tumor growth but not cachexia. We further showed an increase in the infiltration of immune cell population in the IL-6 KO tumors compared with wild-type controls and the defective IL-6 KO tumor growth was rescued in immunodeficient mice while cachexia was not. Thus, IL-6 promotes tumor growth by facilitating immune evasion but is dispensable for cachexia.