RESUMO
The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we show that the 'interleukin 1 (IL-1)-interleukin 1 receptor antagonist (IL-1ra)' axis regulates vaccine-mediated systemic inflammation in a host-specific manner. In human immune cells, RNA vaccines induce production of IL-1 cytokines, predominantly IL-1ß, which is dependent on both the RNA and lipid formulation. IL-1 in turn triggers the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6). Unlike humans, murine leukocytes respond to RNA vaccines by upregulating anti-inflammatory IL-1ra relative to IL-1 (predominantly IL-1α), protecting mice from cytokine-mediated toxicities at >1,000-fold higher vaccine doses. Thus, the IL-1 pathway plays a key role in triggering RNA vaccine-associated innate signaling, an effect that was unexpectedly amplified by certain lipids used in vaccine formulations incorporating N1-methyl-pseudouridine-modified RNA to reduce activation of Toll-like receptor signaling.
Assuntos
Inflamação , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1 , Animais , COVID-19 , Inflamação/imunologia , Inflamação/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-1/genética , Interleucina-1/imunologia , Lipídeos , Camundongos , RNA , Vacinas Sintéticas , Vacinas de mRNA/efeitos adversos , Vacinas de mRNA/metabolismoRESUMO
The acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adenosine monophosphate (cAMP) in tumor-infiltrating monocytes. Here we show that the release of non-toxic concentrations of an adenylate cyclase (AC) inhibitor from poly(sarcosine)-block-poly(L-glutamic acid γ-benzyl ester) (polypept(o)id) copolymer micelles restores antitumor immunity. In combination with selective, non-therapeutic regulatory T cell depletion, AC inhibitor micelles achieve a complete remission of established B16-F10-OVA tumors. Single-cell sequencing of melanoma-infiltrating immune cells shows that AC inhibitor micelles reduce the number of anti-inflammatory myeloid cells and checkpoint receptor expression on T cells. AC inhibitor micelles thus represent an immunotherapeutic measure to counteract melanoma immune escape.
Assuntos
Inibidores de Adenilil Ciclases/farmacologia , Adenilil Ciclases/genética , Antineoplásicos/farmacologia , AMP Cíclico/antagonistas & inibidores , Melanoma Experimental/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Inibidores de Adenilil Ciclases/síntese química , Adenilil Ciclases/imunologia , Animais , Antineoplásicos/síntese química , Compostos de Benzil/química , AMP Cíclico/imunologia , AMP Cíclico/metabolismo , Ésteres , Feminino , Expressão Gênica , Humanos , Imunidade Inata/efeitos dos fármacos , Injeções Intralesionais , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Micelas , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Células Mieloides/patologia , Peptídeos/química , Ácido Poliglutâmico/química , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Sarcosina/análogos & derivados , Sarcosina/química , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Carga Tumoral/efeitos dos fármacos , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
IL-1ß is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1ß contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn-/-), we observed that IL-1ß blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn-/- Tregs and wild-type Tregs differentiated with IL-1ß accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1ß-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.
Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Interleucina-1beta/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Artrite Experimental/etiologia , Artrite Experimental/patologia , Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Diferenciação Celular/imunologia , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/deficiência , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Osteoclastos/imunologia , Osteoclastos/patologia , Osteogênese/imunologia , Ligante RANK/imunologia , Linfócitos T Reguladores/metabolismoRESUMO
Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. Using cells from patients and newly generated mouse models, we uncovered ELF4-mutant macrophages having hyperinflammatory responses to a range of innate stimuli. In mouse macrophages, Elf4 both sustained the expression of anti-inflammatory genes, such as Il1rn, and limited the upregulation of inflammation amplifiers, including S100A8, Lcn2, Trem1 and neutrophil chemoattractants. Blockade of Trem1 reversed inflammation and intestine pathology after in vivo lipopolysaccharide challenge in mice carrying patient-derived variants in Elf4. Thus, ELF4 restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory disorders such as IBD.
Assuntos
Proteínas de Ligação a DNA/genética , Doenças Hereditárias Autoinflamatórias/genética , Doenças Inflamatórias Intestinais/genética , Macrófagos/imunologia , Fatores de Transcrição/genética , Animais , Calgranulina A/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Doenças Hereditárias Autoinflamatórias/imunologia , Doenças Hereditárias Autoinflamatórias/patologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Lipocalina-2/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Th17/imunologia , Transcrição Gênica/genética , Receptor Gatilho 1 Expresso em Células Mieloides/antagonistas & inibidores , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismoRESUMO
Systemic inflammation induced by periodontitis is suggested to be the link between periodontitis and cardiovascular disease. The aim of this work was to explore the oral microbiome in periodontitis in relation to disease severity and systemic inflammation. The saliva and subgingival microbiome from periodontal pocket samples of patients with severe (n = 12) and mild periodontitis (n = 13) were analyzed using metagenomic shotgun sequencing. The taxa and pathways abundances were quantified. The diversity was assessed and the abundances to phenotype associations were performed using ANCOM and linear regression. A panel of inflammatory markers was measured in blood and was associated with taxa abundance. The microbial diversity and species richness did not differ between severe and mild periodontitis in either saliva or periodontal pockets. However, there were significant differences in the microbial composition between severe and mild periodontitis in the subgingival microbiome (i.e., pocket samples) and, in a lower grade, in saliva, and this is positively associated with systemic inflammatory markers. The "red complex" and "cluster B" abundances in periodontal pockets were strongly associated with inflammatory markers interleukin-6 and the white blood cell count. Our data suggest that systemic inflammation in severe periodontitis may be driven by the oral microbiome and may support the indirect (inflammatory) mechanism for the association between periodontitis and cardiovascular disease.
Assuntos
Metagenoma , Microbiota/genética , Periodontite/microbiologia , Periodonto/microbiologia , Idoso , Biomarcadores/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/microbiologia , Doenças Cardiovasculares/patologia , Feminino , Expressão Gênica , Variação Genética , Humanos , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Leucócitos/imunologia , Leucócitos/microbiologia , Masculino , Pessoa de Meia-Idade , Periodontite/complicações , Periodontite/imunologia , Periodontite/patologia , Periodonto/imunologia , Periodonto/patologia , Fenótipo , Filogenia , Índice de Gravidade de DoençaRESUMO
Hepatitis B virus (HBV) vaccines are composed of surface antigen HBsAg that spontaneously assembles into subviral particles. Factors that impede its humoral immunity in 5% to 10% of vaccinees remain elusive. Here, we showed that the low-level interleukin-1 receptor antagonist (IL-1Ra) can predict antibody protection both in mice and humans. Mechanistically, murine IL-1Ra-inhibited T follicular helper (Tfh) cell expansion and subsequent germinal center (GC)-dependent humoral immunity, resulting in significantly weakened protection against the HBV challenge. Compared to soluble antigens, HBsAg particle antigen displayed a unique capture/uptake and innate immune activation, including IL-1Ra expression, preferably of medullary sinus macrophages. In humans, a unique polymorphism in the RelA/p65 binding site of IL-1Ra enhancer associated IL-1Ra levels with ethnicity-dependent vaccination outcome. Therefore, the differential IL-1Ra response to particle antigens probably creates a suppressive milieu for Tfh/GC development, and neutralization of IL-1Ra would resurrect antibody response in HBV vaccine nonresponders.
Assuntos
Imunogenicidade da Vacina/imunologia , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Células T Auxiliares Foliculares/metabolismo , Animais , Anticorpos/imunologia , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Antígenos/imunologia , Linfócitos B/imunologia , Centro Germinativo/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Vacinas contra Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/patogenicidade , Humanos , Imunidade Humoral/imunologia , Imunogenicidade da Vacina/fisiologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-1/imunologia , Receptores de Interleucina-1/metabolismo , Células T Auxiliares Foliculares/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vacinação/métodosRESUMO
OBJECTIVE: To identify novel heterozygous LPIN2 mutations in a patient with Majeed syndrome and characterize the pathomechanisms that lead to the development of sterile osteomyelitis. METHODS: Targeted genetic analysis and functional studies assessing monocyte responses, macrophage differentiation, and osteoclastogenesis were conducted to compare the pathogenesis of Majeed syndrome to interleukin-1 (IL-1)-mediated diseases including neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of the IL-1 receptor antagonist (DIRA). RESULTS: A 4-year-old girl of mixed ethnic background presented with sterile osteomyelitis and elevated acute-phase reactants. She had a 17.8-kb deletion on the maternal LPIN2 allele and a splice site mutation, p.R517H, that variably spliced out exons 10 and 11 on the paternal LPIN2 allele. The patient achieved long-lasting remission receiving IL-1 blockade with canakinumab. Compared to controls, monocytes and monocyte-derived M1-like macrophages from the patient with Majeed syndrome and those with NOMID or DIRA had elevated caspase 1 activity and IL-1ß secretion. In contrast, lipopolysaccharide-stimulated, monocyte-derived, M2-like macrophages from the patient with Majeed syndrome released higher levels of osteoclastogenic mediators (IL-8, IL-6, tumor necrosis factor, CCL2, macrophage inflammatory protein 1α/ß, CXCL8, and CXCL1) compared to NOMID patients and healthy controls. Accelerated osteoclastogenesis in the patient with Majeed syndrome was associated with higher NFATc1 levels, enhanced JNK/MAPK, and reduced Src kinase activation, and partially responded to JNK inhibition and IL-1 (but not IL-6) blockade. CONCLUSION: We report 2 novel compound heterozygous disease-causing mutations in LPIN2 in an American patient with Majeed syndrome. LPIN2 deficiency drives differentiation of proinflammatory M2-like macrophages and enhances intrinsic osteoclastogenesis. This provides a model for the pathogenesis of sterile osteomyelitis which differentiates Majeed syndrome from other IL-1-mediated autoinflammatory diseases.
Assuntos
Anemia Diseritropoética Congênita/genética , Síndromes de Imunodeficiência/genética , Inflamação/genética , Macrófagos/imunologia , Proteínas Nucleares/genética , Osteogênese/genética , Osteomielite/genética , Anemia Diseritropoética Congênita/tratamento farmacológico , Anemia Diseritropoética Congênita/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Estudos de Casos e Controles , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/genética , Síndromes Periódicas Associadas à Criopirina/imunologia , Feminino , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/imunologia , Heterozigoto , Humanos , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/imunologia , Inflamação/imunologia , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , MAP Quinase Quinase 4/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fatores de Transcrição NFATC/metabolismo , Proteínas Nucleares/imunologia , Osteomielite/tratamento farmacológico , Osteomielite/imunologia , Quinases da Família src/metabolismoRESUMO
BACKGROUNDElevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare with those observed in critically ill patients with acute respiratory distress syndrome (ARDS) or sepsis due to other causes.METHODSWe used a Luminex assay to determine expression of 76 cytokines from plasma of hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients. Our analysis focused on detecting statistical differences in levels of 6 cytokines associated with cytokine storm (IL-1ß, IL-1RA, IL-6, IL-8, IL-18, and TNF-α) between patients with moderate COVID-19, severe COVID-19, and ARDS or sepsis.RESULTSFifteen hospitalized COVID-19 patients, 9 of whom were critically ill, were compared with critically ill patients with ARDS (n = 12) or sepsis (n = 16). There were no statistically significant differences in baseline levels of IL-1ß, IL-1RA, IL-6, IL-8, IL-18, and TNF-α between patients with COVID-19 and critically ill controls with ARDS or sepsis.CONCLUSIONLevels of inflammatory cytokines were not higher in severe COVID-19 patients than in moderate COVID-19 or critically ill patients with ARDS or sepsis in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 may be unwarranted.FUNDINGFunding was received from NHLBI K23 HL125663 (AJR); The Bill and Melinda Gates Foundation OPP1113682 (AJR and CAB); Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases #1016687 NIH/NIAID U19AI057229-16; Stanford Maternal Child Health Research Institute; and Chan Zuckerberg Biohub (CAB).
Assuntos
Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/imunologia , Pneumonia Viral/imunologia , Síndrome do Desconforto Respiratório/imunologia , Sepse/imunologia , Adulto , Idoso , COVID-19 , Estudos de Casos e Controles , Infecções por Coronavirus/sangue , Síndrome da Liberação de Citocina/sangue , Citocinas/sangue , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-18/sangue , Interleucina-18/imunologia , Interleucina-1beta/sangue , Interleucina-1beta/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Interleucina-8/sangue , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Síndrome do Desconforto Respiratório/sangue , Sepse/sangue , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: Identifying immune correlates of COVID-19 disease severity is an urgent need for clinical management, vaccine evaluation, and drug development. Here, we present a temporal analysis of key immune mediators, cytokines, and chemokines in blood of hospitalized COVID-19 patients from serial sampling and follow-up over 4 weeks. METHODS: A total of 71 patients with laboratory-confirmed COVID-19 admitted to Beijing You'an Hospital in China with either mild (53 patients) or severe (18 patients) disease were enrolled with 18 healthy volunteers. We measured 34 immune mediators, cytokines, and chemokines in peripheral blood every 4-7 days over 1 month per patient using a bioplex multiplex immunoassay. RESULTS: We found that the chemokine RANTES (CCL5) was significantly elevated, from an early stage of the infection, in patients with mild but not severe disease. We also found that early production of inhibitory mediators including IL-10 and IL-1RA were significantly associated with disease severity, and a combination of CCL5, IL-1 receptor antagonist (IL-1RA), and IL-10 at week 1 may predict patient outcomes. The majority of cytokines that are known to be associated with the cytokine storm in virus infections such as IL-6 and IFN-γ were only significantly elevated in the late stage of severe COVID-19 illness. TNF-α and GM-CSF showed no significant differences between severe and mild cases. CONCLUSION: Together, our data suggest that early intervention to increase expression of CCL5 may prevent patients from developing severe illness. Our data also suggest that measurement of levels of CCL5, as well as IL-1RA and IL-10 in blood individually and in combination, might be useful prognostic biomarkers to guide treatment strategies.
Assuntos
Quimiocina CCL5/imunologia , Infecções por Coronavirus/imunologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-10/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Betacoronavirus , COVID-19 , Estudos de Casos e Controles , Infecções por Coronavirus/fisiopatologia , Síndrome da Liberação de Citocina/imunologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Hospitalização , Humanos , Imunoensaio , Interferon gama/imunologia , Interleucina-6/imunologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/fisiopatologia , SARS-CoV-2 , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Sexually transmitted infections (STIs) and vaginal dysbiosis (disturbed resident microbiota presenting with abnormal Nugent score or candidiasis) have been associated with mucosal inflammation and risk of HIV-1 infection, cancer and poor reproductive outcomes. To date, the temporal relationships between aberrant cervical innate immunity and the clinical onset of microbial disturbance have not been studied in a large population of reproductive age women. We examined data from a longitudinal cohort of 934 Ugandan and Zimbabwean women contributing 3,274 HIV-negative visits who had complete laboratory, clinical and demographic data. Among those, 207 women later acquired HIV, and 584 women were intermittently diagnosed with C. trachomatis (CT), N. gonorrhoeae (NG), genital herpes (HSV-2), T. vaginalis (TV), candidiasis, and abnormal intermediate (4-6) or high (7-10) Nugent score, i.e. bacterial vaginosis (BV). Immune biomarker concentrations in cervical swabs were analyzed by generalized linear and mixed effect models adjusting for site, age, hormonal contraceptive use (HC), pregnancy, breastfeeding, genital practices, unprotected sex and overlapping infections. High likelihood ratios (1.5-4.9) denoted the values of cervical immune biomarkers to predict onset of abnormal Nugent score and candidiasis at the next visits. When controlling for covariates, higher levels of ß-defensin-2 were antecedent to BV, CT and HSV-2, lower anti-inflammatory ratio IL-1RA:IL-1ß-to intermediate Nugent scores and candida, lower levels of the serine protease inhibitor SLPI-to candida, lower levels of the adhesion molecule ICAM-1 -to TV, and lower levels of the oxidative stress mitigator and endothelial activation marker VEGF-to NG. Changes in innate immunity following onset of dysbiosis and infections were dependent on HC use when controlling for all other covariates. In conclusion, imminent female genital tract dysbiosis or infection can be predicted by distinct patterns of innate immunity. Future research should characterize biotic and abiotic determinants of this pre-existing innate immunity state.
Assuntos
Disbiose/imunologia , Imunidade Inata/genética , Infecções Sexualmente Transmissíveis/imunologia , Vaginose Bacteriana/imunologia , Adolescente , Adulto , Biomarcadores/metabolismo , Colo do Útero/imunologia , Colo do Útero/microbiologia , Colo do Útero/patologia , Disbiose/epidemiologia , Disbiose/microbiologia , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Estresse Oxidativo/imunologia , Gravidez , Infecções do Sistema Genital/epidemiologia , Infecções do Sistema Genital/imunologia , Inibidor Secretado de Peptidases Leucocitárias/imunologia , Inibidor Secretado de Peptidases Leucocitárias/metabolismo , Infecções Sexualmente Transmissíveis/epidemiologia , Infecções Sexualmente Transmissíveis/microbiologia , Uganda/epidemiologia , Vagina/imunologia , Vagina/microbiologia , Vaginose Bacteriana/epidemiologia , Vaginose Bacteriana/microbiologia , Fator A de Crescimento do Endotélio Vascular/imunologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Zimbábue/epidemiologiaRESUMO
Toll-like receptor 3 (TLR3) is a sensor of endogenous cell necrosis during the process of acute inflammation. Interleukin (IL)-1 receptor antagonist (IL-1Ra) is an anti-inflammatory cytokine and can negatively regulate the pathogenesis of inflammation. However, whether and how activation of TLR3 can regulate IL-1Ra expression has not been clarified. Here, we show that poly(I:C) induces IL-1Ra expression in primarily cultured human fibroblast-like synoviocytes and other types of cells. Induction of IL-1Ra by poly(I:C) was dependent on TLR3, but was independent of melanoma differentiation--associated protein 5 or retinoic acid-inducible gene I. Interferon regulatory factor 3 (IRF3) directly binds to the IL-1Ra promoter and promotes IL-1Ra expression in response to poly(I:C) stimulation. Induction of IL-1Ra by poly(I:C) was abolished by the inhibition of the NF-κB signaling, attenuated by the inhibition of the PI3K-Akt signaling, enhanced by inhibition of the ERK1/2 or MSK1/2 activation, but was independent of the p38 MAPK signaling. Treatment with poly(I:C) or Sendai virus elevated the levels of serum IL-1Ra in wild-type, but not in TLR3-/- or IRF3-/- mice. Our findings may provide new insights into the intrinsic anti-inflammatory function of TLR3 and double-stranded RNA-induced IL-Ra expression by TLR3 and its regulation.
Assuntos
Proteína Antagonista do Receptor de Interleucina 1/imunologia , Receptor 3 Toll-Like/imunologia , Animais , Linhagem Celular , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Fator Regulador 3 de Interferon/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Camundongos , Camundongos Knockout , Poli I-C/farmacologia , Receptor 3 Toll-Like/genéticaRESUMO
Interleukin (IL)-1 receptor antagonist (IL-1Ra), a naturally occurring antagonist of IL-1α/IL-1ß signaling pathways, has been attributed to the immunosuppressive effects of mesenchymal stem cells (MSCs). MSCs, in IL-1Ra-dependent manner, suppressed production of IL-1ß in dermal macrophages, induced their polarization in anti-inflammatory M2 phenotype, attenuated antigen-presenting properties of dendritic cells (DCs), and promoted expansion of immunosuppressive T regulatory cells in the skin, which resulted in enhanced repair of the nonhealing wounds. Reduced activation of inflammasome and suppressed production of IL-1ß in macrophages were mainly responsible for beneficial effects of MSC-derived IL-1Ra in alleviation of acute lung injury, dry eye syndrome, and corneal injury. Through the production of IL-1Ra, MSCs reduced migration of DCs to the draining lymph nodes and attenuated generation of inflammatory Th1 and Th17 cells that resulted in alleviation of fulminant hepatitis and rheumatoid arthritis. MSCs, in IL-1Ra-dependent manner, reduced liver fibrosis by suppressing production of Type I collagen in hepatic stellate cells. IL-1Ra was, at least partially, responsible for enhanced proliferation of hepatocytes and chondrocytes in MSC-treated animals with partial hepatectomy and osteoarthritis. Despite of these beneficial effects, IL-1Ra-dependent inhibition of IL-1α/IL-1ß-signaling significantly increased risk of infections. Therefore, future experimental and clinical studies should delineate potential side effects of MSC-derived IL-1Ra before IL-1Ra-overexpressing MSCs could be used as a potentially new therapeutic agent for the treatment of acute and chronic inflammatory diseases.
Assuntos
Proliferação de Células/fisiologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Células-Tronco Mesenquimais/imunologia , Regeneração/imunologia , Regeneração/fisiologia , Humanos , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Células-Tronco Mesenquimais/metabolismoRESUMO
There exists little human neuroscience research to explain why some individuals lose their appetite when they become depressed, while others eat more. Answering this question may reveal much about the various pathophysiologies underlying depression. The present study combined neuroimaging, salivary cortisol, and blood markers of inflammation and metabolism collected prior to scanning. We compared the relationships between peripheral endocrine, metabolic, and immune signaling and brain activity to food cues between depressed participants experiencing increased (N = 23) or decreased (N = 31) appetite and weight in their current depressive episode and healthy control participants (N = 42). The two depression subgroups were unmedicated and did not differ in depression severity, anxiety, anhedonia, or body mass index. Depressed participants experiencing decreased appetite had higher cortisol levels than subjects in the other two groups, and their cortisol values correlated inversely with the ventral striatal response to food cues. In contrast, depressed participants experiencing increased appetite exhibited marked immunometabolic dysregulation, with higher insulin, insulin resistance, leptin, CRP, IL-1RA, and IL-6, and lower ghrelin than subjects in other groups, and the magnitude of their insulin resistance correlated positively with the insula response to food cues. These findings provide novel evidence linking aberrations in homeostatic signaling pathways within depression subtypes to the activity of neural systems that respond to food cues and select when, what, and how much to eat. In conjunction with prior work, the present findings strongly support the existence of pathophysiologically distinct depression subtypes for which the direction of appetite change may be an easily measured behavioral marker.
Assuntos
Apetite , Depressão/imunologia , Depressão/metabolismo , Adolescente , Adulto , Apetite/imunologia , Proteína C-Reativa/análise , Depressão/sangue , Depressão/classificação , Feminino , Grelina/sangue , Humanos , Hidrocortisona/análise , Inflamação/sangue , Inflamação/complicações , Inflamação/imunologia , Insulina/sangue , Insulina/metabolismo , Resistência à Insulina , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Saliva/química , Adulto JovemRESUMO
IL-25, a member of the IL-17 family of cytokines, is known to enhance type 2 immune responses, but suppress type 3 (IL-17A)-mediated immune responses. Mice deficient in IL-1 receptor antagonist (Il1rn-/- mice) have excessive IL-1 signaling, resulting in spontaneous development of IL-1-, TNF- and IL-17A-dependent aortitis. We found that expression of II25 mRNA was increased in the aortae of Il1rn-/- mice, suggesting that IL-25 may suppress development of IL-1-, TNF- and IL-17A-dependent aortitis in Il1rn-/- mice by inhibiting type 3-mediated immune responses. However, we unexpectedly found that Il25-/-Il1rn-/- mice showed attenuated development of aortitis, accompanied by reduced accumulation of inflammatory cells such as dendritic cells, macrophages and neutrophils and reduced mRNA expression of Il17a and Tnfa-but not Il4 or Il13-in local lesions compared with Il1rn-/- mice. Tissue-, but not immune cell-, derived IL-25 was crucial for development of aortitis. IL-25 enhanced IL-1ß and TNF production by IL-25 receptor-expressing dendritic cells and macrophages, respectively, at inflammatory sites of aortae of Il1rn-/- mice, contributing to exacerbation of development of IL-1-, TNF- and IL-17A-dependent aortitis in those mice. Our findings suggest that neutralization of IL-25 may be a potential therapeutic target for aortitis.
Assuntos
Aortite/imunologia , Doenças Autoimunes/imunologia , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucinas/imunologia , Animais , Aortite/genética , Aortite/patologia , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Células Dendríticas/imunologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-17/genética , Interleucina-1beta/metabolismo , Interleucinas/genética , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neutrófilos/imunologia , RNA Mensageiro/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The bacterium Mycobacterium tuberculosis (Mtb) causes tuberculosis and is responsible for more human mortality than any other single pathogen1. Progression to active disease occurs in only a fraction of infected individuals and is predicted by an elevated type I interferon (IFN) response2-7. Whether or how IFNs mediate susceptibility to Mtb has been difficult to study due to a lack of suitable mouse models6-11. Here, we examined B6.Sst1S congenic mice that carry the 'susceptible' allele of the Sst1 locus that results in exacerbated Mtb disease12-14. We found that enhanced production of type I IFNs was responsible for the susceptibility of B6.Sst1S mice to Mtb. Type I IFNs affect the expression of hundreds of genes, several of which have previously been implicated in susceptibility to bacterial infections6,7,15-18. Nevertheless, we found that heterozygous deficiency in just a single IFN target gene, Il1rn, which encodes interleukin-1 receptor antagonist (IL-1Ra), is sufficient to reverse IFN-driven susceptibility to Mtb in B6.Sst1S mice. In addition, antibody-mediated neutralization of IL-1Ra provided therapeutic benefit to Mtb-infected B6.Sst1S mice. Our results illustrate the value of the B6.Sst1S mouse to model IFN-driven susceptibility to Mtb, and demonstrate that IL-1Ra is an important mediator of type I IFN-driven susceptibility to Mtb infections in vivo.
Assuntos
Predisposição Genética para Doença , Interferon Tipo I/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Receptores de Somatostatina/genética , Tuberculose/genética , Alelos , Animais , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Interferon Tipo I/imunologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Congênicos , Organismos Livres de Patógenos Específicos , Tuberculose/imunologiaRESUMO
OBJECTIVE: To test the hypothesis that acute elevations in serum inflammatory markers predict symptom recovery after sport-related concussion (SRC). METHODS: High school and collegiate football players (n = 857) were prospectively enrolled. Forty-one athletes with concussion and 43 matched control athletes met inclusion criteria. Serum levels of interleukin (IL)-6, IL-1ß, IL-10, tumor necrosis factor, C-reactive protein, interferon-γ, and IL-1 receptor antagonist and Sport Concussion Assessment Tool, 3rd edition (SCAT3) symptom severity scores were collected at a preinjury baseline, 6 and 24-48 hours postinjury, and approximately 8, 15, and 45 days following concussion. The number of days that athletes were symptomatic following SRC (i.e., duration of symptoms) was the primary outcome variable. RESULTS: IL-6 and IL-1RA were significantly elevated in athletes with concussion at 6 hours relative to preinjury and other postinjury visits, as well as compared to controls (ps ≤ 0.001). IL-6 and IL-1RA significantly discriminated concussed from control athletes at 6 hours postconcussion (IL-6 area under receiver operating characteristic curve 0.79 [95% confidence interval (CI) 0.65-0.92], IL-1RA AUC 0.79 [95% CI 0.67-0.90]). Further, IL-6 levels at 6 hours postconcussion were significantly associated with the duration of symptoms (hazard ratio for symptom recovery = 0.61 [95% CI 0.38-0.96], p = 0.031). CONCLUSIONS: Results support the potential utility of IL-6 and IL-1RA as serum biomarkers of SRC and demonstrate the potential of these markers in identifying athletes at risk for prolonged recovery after SRC. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that serum levels of IL-6 and IL-1RA 6 hours postconcussion significantly discriminated concussed from control athletes.
Assuntos
Traumatismos em Atletas/imunologia , Concussão Encefálica/imunologia , Citocinas/imunologia , Futebol Americano/lesões , Adolescente , Atletas , Traumatismos em Atletas/fisiopatologia , Concussão Encefálica/fisiopatologia , Proteína C-Reativa/imunologia , Humanos , Interferon gama/imunologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-10/imunologia , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Masculino , Prognóstico , Recuperação de Função Fisiológica , Fator de Necrose Tumoral alfa/imunologia , Adulto JovemRESUMO
The NLRP3 inflammasome, IL-1ß release and pyroptosis (cell lysis) have recently been proposed to be essential for the progression of urinary tract infection (UTI) and elimination of intracellular bacterial niches. However, the effects of IL-1R antagonist (IL-1RA) on immune responses during UTI, except for its ability to disrupt IL-1ß signalling, are not well understood. The aim of this study was to investigate the role of IL-1RA in UPEC colonization of bladder epithelial cells and the subsequent host inflammatory response. Human bladder epithelial cells (5637) and CRISPR/Cas9 generated NLRP3 and caspase-1 knockdown cells and IL-1RA knockout cells were stimulated with the UPEC isolate CFT073. The results showed that the UPEC virulence factor α-hemolysin is essential for IL-1RA release, and that the inflammasome-associated proteins caspase-1 and NLRP3 affect the release of IL-1RA. IL-1RA deficient cells showed a reduced adherence and invasion by CFT073 compared to wild-type cells, suggesting that IL-1RA may oppose mechanisms that protects against bacterial colonization. A targeted protein analysis of inflammation-related proteins showed that the basal expression of 23 proteins and the UPEC-induced expression of 10 proteins were significantly altered in IL-1RA deficient bladder epithelial cells compared to Cas9 control cells. This suggests that IL-1RA has a broad effect on the inflammatory response in bladder epithelial cells.
Assuntos
Células Epiteliais/imunologia , Infecções por Escherichia coli/imunologia , Inflamassomos/imunologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Bexiga Urinária/imunologia , Infecções Urinárias/imunologia , Escherichia coli Uropatogênica/imunologia , Linhagem Celular , Células Epiteliais/microbiologia , Infecções por Escherichia coli/patologia , Humanos , Bexiga Urinária/microbiologia , Bexiga Urinária/patologia , Infecções Urinárias/microbiologia , Infecções Urinárias/patologiaRESUMO
This special edition of the Biomedical Journal puts the innate immune system into the limelight. We learn about the universal mechanisms underlying the immediate defense against influenza viruses mounted by innate immunity but also its detrimental secondary effects and how differential host genetics influence the network. Moreover, this issue addresses how oral hygiene is a concern for the entire organism, that younger age goes well with neoadjuvant chemotherapy for breast cancer and zinc with feeling less distressed by tinnitus caused by noise-induced hearing loss, and that IL-1Ra holds very promising potential to prevent intestinal ischemia reperfusion injury. Finally, we discover which type of post optimally protects devitalized teeth from breaking and how difficult it is to accurately diagnose the macrofollicular variant of papillary thyroid carcinoma.
Assuntos
Imunidade Inata/imunologia , Influenza Humana/virologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Traumatismo por Reperfusão/virologia , Animais , Humanos , Influenza Humana/imunologia , Traumatismo por Reperfusão/imunologiaRESUMO
Bronchopulmonary dysplasia (BPD) remains a devastating consequence of prematurity. Repeated inflammatory insults worsen lung injury, but there are no predictors for BPD-related respiratory outcomes or targeted therapies. We sought to understand inflammatory mechanisms in evolving BPD through molecular characterization of monocytes in tracheal aspirates from infants at risk for developing BPD. We performed flow cytometry targeting myeloid cell populations on prospectively collected tracheal aspirates from intubated patients born before 29 wk of gestation and <30 days old. We identified CD14+CD16+ (double-positive) and CD14+CD16- (single-positive) monocytes and characterized their gene expression profiles by RNA sequencing and quantitative PCR. We further analyzed differential gene expression between time points to evaluate changes in monocyte function over the first weeks of life. Expression of IL-1A, IL-1B, and IL-1 receptor antagonist mRNA was increased in monocytes collected at day of life (DOL) 7, DOL 14, and DOL 28 compared with those collected at DOL 3. This study suggests that early changes in monocyte-specific IL-1 cytokine pathways may be associated with evolving BPD.
Assuntos
Displasia Broncopulmonar/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1alfa/genética , Interleucina-1beta/genética , Monócitos/imunologia , RNA Mensageiro/genética , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Displasia Broncopulmonar/imunologia , Displasia Broncopulmonar/patologia , Feminino , Proteínas Ligadas por GPI/deficiência , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Regulação da Expressão Gênica , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-1alfa/imunologia , Interleucina-1beta/imunologia , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/imunologia , Masculino , Monócitos/patologia , Projetos Piloto , Estudos Prospectivos , RNA Mensageiro/imunologia , Receptores de IgG/deficiência , Receptores de IgG/genética , Receptores de IgG/imunologia , Análise de Sequência de RNA , Transdução de Sinais , Traqueia/imunologia , Traqueia/patologiaRESUMO
The IL-1 family comprises two anti-inflammatory cytokines (IL-37, IL-38), two receptor antagonists (IL-1ra, IL-36ra), and seven ligand agonists (IL-1α, IL-1ß, IL-33, IL-36α, IL-36ß, IL-36γ). The members of this family exert pleiotropic effects on intercellular signaling, leading to pro- or anti-inflammatory responses. They initiate potent inflammatory and immune responses by binding to specific receptors in the IL-1 receptor family, and their activities are repressed by naturally occurring inhibitors. Various immune cells produce and are regulated by these crucial molecules, which appear to be involved in the pathogenesis of diverse diseases including cancer as well as inflammatory and autoimmune disorders. Recent decades have seen substantial progress in understanding how the IL-1 family contributes to the development of sepsis. In this review, we will briefly introduce the IL-1 family and discuss its critical role in inflammatory and immune responses. The potential significance of IL-1 members in sepsis will also be explored, together with the clinical implications for treating this dangerous condition.