RESUMO
In lupus, Toll-like receptor 7 (TLR7) and TLR9 mediate loss of tolerance to RNA and DNA, respectively. Yet, TLR7 promotes disease, while TLR9 protects from disease, implying differences in signaling. To dissect this 'TLR paradox', we generated two TLR9 point mutants (lacking either ligand (TLR9K51E) or MyD88 (TLR9P915H) binding) in lupus-prone MRL/lpr mice. Ameliorated disease of Tlr9K51E mice compared to Tlr9-/- controls revealed a TLR9 'scaffold' protective function that is ligand and MyD88 independent. Unexpectedly, Tlr9P915H mice were more protected than both Tlr9K51E and Tlr9WT mice, suggesting that TLR9 also possesses ligand-dependent, but MyD88-independent, regulatory signaling and MyD88-mediated proinflammatory signaling. Triple-mixed bone marrow chimeras showed that TLR9-MyD88-independent regulatory roles were B cell intrinsic and restrained differentiation into pathogenic age-associated B cells and plasmablasts. These studies reveal MyD88-independent regulatory roles of TLR9, shedding light on the biology of endosomal TLRs.
Assuntos
Receptor 7 Toll-Like , Receptor Toll-Like 9 , Animais , DNA , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , RNA , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismoRESUMO
Oropharyngeal candidiasis (OPC) is an opportunistic infection of the oral mucosa caused by the commensal fungus Candida albicans IL-17R signaling is essential to prevent OPC in mice and humans, but the individual roles of its ligands, IL-17A, IL-17F, and IL-17AF, are less clear. A homozygous IL-17F deficiency in mice does not cause OPC susceptibility, whereas mice lacking IL-17A are moderately susceptible. In humans, a rare heterozygous mutation in IL-17F (IL-17F.S65L) was identified that causes chronic mucocutaneous candidiasis, suggesting the existence of essential antifungal pathways mediated by IL-17F and/or IL-17AF. To investigate the role of IL-17F and IL-17AF in more detail, we exploited this "experiment of nature" by creating a mouse line bearing the homologous mutation in IL-17F (Ser65Leu) by CRISPR/Cas9. Unlike Il17f-/- mice that are resistant to OPC, Il17fS65L/S65L mice showed increased oral fungal burdens similar to Il17a -/- mice. In contrast to humans, however, disease was only evident in homozygous, not heterozygous, mutant mice. The mutation was linked to modestly impaired CXC chemokine expression and neutrophil recruitment to the infected tongue but not to alterations in oral antimicrobial peptide expression. These findings suggest mechanisms by which the enigmatic cytokine IL-17F contributes to host defense against fungi. Moreover, because these mice do not phenocopy Il17f-/- mice, they may provide a valuable tool to interrogate IL-17F and IL-17AF function in vivo in other settings.
Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Interleucina-17/imunologia , Doenças da Boca/imunologia , Animais , Candida albicans/genética , Candidíase/genética , Candidíase/patologia , Técnicas de Introdução de Genes , Interleucina-17/genética , Camundongos , Camundongos Transgênicos , Doenças da Boca/genética , Doenças da Boca/microbiologia , Doenças da Boca/patologia , Mutação de Sentido IncorretoRESUMO
An important function of immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors is cross-regulation of heterologous receptor signaling, but mechanisms of cross-inhibition are poorly understood. We show that high-avidity ligation of ITAM-coupled beta2 integrins and FcgammaRs in macrophages inhibited type I interferon receptor and Toll-like receptor (TLR) signaling and induced expression of interleukin-10 (IL-10); signaling inhibitors SOCS3, ABIN-3, and A20; and repressors of cytokine gene transcription STAT3 and Hes1. Induction of inhibitors was dependent on a pathway composed of signaling molecules DAP12, Syk, and Pyk2 that coupled to downstream kinases p38 and MSKs and required integration of IL-10-dependent and -independent signals. ITAM-induced inhibitors abrogated TLR responses by cooperatively targeting distinct steps in TLR signaling. Inhibitory signaling was suppressed by IFN-gamma and attenuated in inflammatory arthritis synovial macrophages. These results provide an indirect mechanism of cross-inhibition of TLRs and delineate a signaling pathway important for deactivation of macrophages.
Assuntos
Antígenos CD18/imunologia , Interferon Tipo I/imunologia , Receptores Imunológicos/imunologia , Receptores Toll-Like/imunologia , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Células Cultivadas , Quinase 2 de Adesão Focal/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais , Quinase Syk , Receptores Toll-Like/metabolismoRESUMO
The trigeminal nerve or fifth cranial nerve has an extensive distribution in the head and face. It is the source for pain conduction and thereby is often implicated in a variety of disorders including inflammatory and neoplastic diseases. To determine the disease source, understanding the trigeminal nerve anatomy is essential, and further being able to image the trigeminal nerve provides insight into the location and type of pathology. The best approach to imaging is to consider the nerve in segments. The nerve segments may be divided into the brainstem, cisternal, Meckel's cave, cavernous sinus, and peripheral divisions. This review utilizes these segments to explore imaging options to help understand trigeminal neuralgia and pain in the trigeminal nerve distribution.
Assuntos
Angiografia Cerebral , Neoplasias dos Nervos Cranianos/diagnóstico , Dor Facial/diagnóstico , Imageamento por Ressonância Magnética , Boca/patologia , Nervo Trigêmeo/patologia , Neuralgia do Trigêmeo/diagnóstico , Meios de Contraste , Neoplasias dos Nervos Cranianos/complicações , Dor Facial/etiologia , Dor Facial/patologia , Humanos , Nervo Trigêmeo/anatomia & histologia , Neuralgia do Trigêmeo/etiologia , Neuralgia do Trigêmeo/patologiaRESUMO
OBJECTIVES: Sjögren's disease (SjD) is a heterogenous disease with a wide range of manifestations, ranging from symptoms of dryness, fatigue, and pain, to systemic involvement. Considerable advances have been made to evaluate systemic activity or patient-reported outcomes, but most of the instruments were not able to assess all domains of this multifaceted disease. The aim of this scoping review was to generate domains that have been assessed in randomized controlled trials, as the first phase of the Outcome Measures in Rheumatology (OMERACT) process of core domain set development. METHODS: We systematically searched Medline (Pubmed) and EMBASE between 2002 and March 2023 to identify all randomized controlled trials assessing relevant domains, using both a manual approach and an artificial intelligence software (BIBOT) that applies natural language processing to automatically identify relevant abstracts. Domains were mapped to core areas, as suggested by the OMERACT 2.1 Filter. RESULTS: Among the 5,420 references, we included 60 randomized controlled trials, focusing either on overall disease manifestations (53%) or on a single organ/symptom: dry eyes (17%), xerostomia (15%), fatigue (12%), or pulmonary function (3%). The most frequently assessed domains were perceived dryness (52% for overall dryness), fatigue (57%), pain (52%), systemic disease activity (45%), lacrimal gland function (47%) and salivary function (55%), B-cell activation (60%), and health-related quality of life (40%). CONCLUSION: Our scoping review highlighted the heterogeneity of SjD, in the study designs and domains. This will inform the OMERACT SjD working group to select the most appropriate core domains to be used in SjD clinical trials and to guide the future agenda for outcome measure research in SjD.
Assuntos
Qualidade de Vida , Síndrome de Sjogren , Humanos , Inteligência Artificial , Fadiga/etiologia , Dor , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Loss of NADPH oxidase (NOX2) exacerbates systemic lupus erythematosus (SLE) in mice and humans, but the mechanisms underlying this effect remain unclear. To identify the cell lineages in which NOX2 deficiency drives SLE, we employed conditional KO and chimeric approaches to delete Cybb in several hematopoietic cell lineages of MRL.Faslpr SLE-prone mice. Deletion of Cybb in macrophages/monocytes exacerbated SLE nephritis, though not to the degree observed in the Cybb global KOs. Unexpectedly, the absence of Cybb in B cells resulted in profound glomerulonephritis and interstitial nephritis, rivaling that seen with global deletion. Furthermore, we identified that NOX2 is a key regulator of TLR7, a driver of SLE pathology, both globally and specifically in B cells. This is mediated in part through suppression of TLR7-mediated NF-κB signaling in B cells. Thus, NOX2's immunomodulatory effect in SLE is orchestrated not only by its function in the myeloid compartment, but through a pivotal role in B cells by selectively inhibiting TLR7 signaling.
Assuntos
Linfócitos B , Lúpus Eritematoso Sistêmico , Macrófagos , Camundongos Knockout , NADPH Oxidase 2 , Receptor 7 Toll-Like , Animais , Receptor 7 Toll-Like/metabolismo , Receptor 7 Toll-Like/genética , Camundongos , Linfócitos B/imunologia , Linfócitos B/metabolismo , NADPH Oxidase 2/metabolismo , NADPH Oxidase 2/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Transdução de Sinais , Feminino , Modelos Animais de Doenças , NF-kappa B/metabolismo , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Nefrite Lúpica/metabolismo , Nefrite Lúpica/genética , Glicoproteínas de MembranaRESUMO
OBJECTIVE: To describe the evolution of the OMERACT Fellows Program (OM FP) and to evaluate the innovative changes implemented in the 2023 program. METHODS: The OM FP, the first of its kind in global rheumatology, was developed in 2000 to mentor early career researchers in methods and processes for reaching evidence-driven consensus for outcome measures in clinical studies. The OM FP has evolved through continuing iterations of face to face and online feedback. Key new features delivered in 2023 included e-learning modules, virtual introductory pre-meetings, increased networking with Patient Research Partners (PRPs), learning opportunities to give and receive personal feedback, ongoing performance feedback during the meeting from Fellow peers, PRPs, senior OMERACTers (members of the OMERACT community) and Emerging Leader mentors, involvement in pitching promotions, two-minute Lightning Talks in a plenary session and an embedded poster tour. An online survey was distributed after the meeting to evaluate the program. RESULTS: OM FP has included 208 fellows from 16 countries across 4 continents covering 47 different aspects of rheumatology outcomes since its inception. Over 50 % have remained engaged with OMERACT work. In 2023, 18 Fellows attended and 15 (83 %) completed the post-meeting survey. A dedicated OM FP was deemed important by all respondents, and 93 % would attend the meeting in future. The PRP/Fellow Connection Carousel and Lightning Talks were rated exceptional by 93 %. Key components to improve included clarification of expectations, overall workload, the Emerging Leaders Mentoring Program, and the content and duration of daily summary sessions. CONCLUSION: The innovations in the 2023 OM FP were well received by the majority of participants and supports early career rheumatology researchers to develop collaborations, skills and expertise in outcome measurement. Implementation of feedback from Fellows will enhance the program for future meetings, continuing to facilitate learning and succession planning within OMERACT.
Assuntos
Reumatologia , Humanos , Mentores , Avaliação de Resultados em Cuidados de Saúde , Consenso , PesquisadoresRESUMO
Sjögren's disease (SjD) is a systemic autoimmune exocrinopathy with key features of dryness, pain, and fatigue. SjD can affect any organ system with a variety of presentations across individuals. This heterogeneity is one of the major barriers for developing effective disease modifying treatments. Defining core disease domains comprising both specific clinical features and incorporating the patient experience is a critical first step to define this complex disease. The OMERACT SjD Working Group held its first international collaborative hybrid meeting in 2023, applying the OMERACT 2.2 filter toward identification of core domains. We accomplished our first goal, a scoping literature review that was presented at the Special Interest Group held in May 2023. Building on the domains identified in the scoping review, we uniquely deployed multidisciplinary experts as part of our collaborative team to generate a provisional domain list that captures SjD heterogeneity.
Assuntos
Síndrome de Sjogren , Humanos , Resultado do Tratamento , Síndrome de Sjogren/terapia , Dor , FadigaRESUMO
OBJECTIVE: Type I interferons (IFNs) have emerged as potential activators of the IFN signature and elevated STAT-1 expression in rheumatoid arthritis (RA) synovium, but mechanisms that induce synovial IFN expression are unknown. Recently, tumor necrosis factor α (TNFα) was shown to induce a delayed IFN response in macrophages. We undertook this study to test whether TNFα, classically thought to activate inflammatory NF-κB target genes in RA, also contributes to the "IFN signature" in RA synovial macrophages. METHODS: Synovial fluid (SF) macrophages purified from 24 patients with RA and 18 patients with spondylarthritides (SpA) were lysed immediately after isolation or were cultured ex vivo in the absence or presence of blockade of endogenous type I IFN or TNFα. Expression of IFN-inducible target genes was measured by quantitative reverse transcription-polymerase chain reaction, and expression of their corresponding proteins was measured by enzyme-linked immunosorbent assay. RESULTS: Expression of an IFN signature and STAT1 in RA synovial macrophages was suppressed when type I IFNs or TNFα were blocked, whereas TNFα blockade did not affect expression of IFN response genes or STAT1 in SpA synovial macrophages. RA SF suppressed the IFN signature in RA synovial macrophages and in TNFα-, IFNα-, and IFNß-stimulated control macrophages. Type I IFNs suppressed expression of IL8 and MMP9 in RA synovial macrophages and in TNFα-stimulated control macrophages. CONCLUSION: Our findings identify a new function of TNFα in RA synovitis by implicating TNFα as a major inducer of the RA synovial IFN response. The results suggest that the expression of IFN response genes in RA synovium is regulated by interplay between TNFα and opposing homeostatic factors expressed in the synovial microenvironment.
Assuntos
Artrite Reumatoide/metabolismo , Interferon Tipo I/metabolismo , Macrófagos/metabolismo , Fator de Transcrição STAT1/metabolismo , Líquido Sinovial/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Humanos , Interferon Tipo I/antagonistas & inibidores , Interferon Tipo I/genética , Interleucina-8/genética , Interleucina-8/metabolismo , Macrófagos/patologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Fator de Transcrição STAT1/genética , Espondilartrite/genética , Espondilartrite/metabolismo , Espondilartrite/patologia , Líquido Sinovial/citologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genéticaRESUMO
Nucleic acid-specific Toll-like receptors (TLRs) have been implicated in promoting disease pathogenesis in systemic lupus erythematosus (SLE). Whether such TLRs mediate disease onset, progression, or both remains undefined; yet the answer to this question has important therapeutic implications. MyD88 is an essential adaptor that acts downstream of IL-1 family receptors and most TLRs. Both global and B cell-specific Myd88 deficiency ameliorated disease in lupus-prone mice when constitutively deleted. To address whether Myd88 was needed to sustain ongoing disease, we induced B cell-specific deletion of Myd88 after disease onset in MRL.Faslpr mice using an inducible Cre recombinase. B cell-specific deletion of Myd88 starting after disease onset resulted in ameliorated glomerulonephritis and interstitial inflammation. Additionally, treated mice had reduced autoantibody formation and an altered B cell compartment with reduced ABC and plasmablast numbers. These experiments demonstrate the role of MyD88 in B cells to sustain disease in murine lupus. Therefore, targeting MyD88 or its upstream activators may be a viable therapeutic option in SLE.
Assuntos
Lúpus Eritematoso Sistêmico , Fator 88 de Diferenciação Mieloide , Camundongos , Animais , Fator 88 de Diferenciação Mieloide/genética , Transdução de Sinais , Linfócitos B , Lúpus Eritematoso Sistêmico/genética , Receptores Toll-Like/metabolismo , Progressão da DoençaRESUMO
IL-27 is a pleiotropic cytokine with both activating and inhibitory functions on innate and acquired immunity. IL-27 is expressed at sites of inflammation in cytokine-driven autoimmune/inflammatory diseases, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, and sarcoidosis. However, its role in modulating disease pathogenesis is still unknown. In this study, we found that IL-27 production is induced by TNF-α in human macrophages (MΦ) and investigated the effects of IL-27 on the responses of primary human MΦ to the endogenous inflammatory cytokines TNF-α and IL-1. In striking contrast to IL-27-mediated augmentation of TLR-induced cytokine production, we found that IL-27 suppressed MΦ responses to TNF-α and IL-1ß, thus identifying an anti-inflammatory function of IL-27. IL-27 blocked the proximal steps of TNF-α signaling by downregulating cell-surface expression of the signaling receptors p55 and p75. The mechanism of inhibition of IL-1 signaling was downregulation of the ligand-binding IL-1RI concomitant with increased expression of the receptor antagonist IL-1Ra and the decoy receptor IL-1RII. These findings provide a mechanism for suppressive effects of IL-27 on innate immune cells and suggest that IL-27 regulates inflammation by limiting activation of MΦ by inflammatory cytokines while preserving initial steps in host defense by augmenting responses to microbial products.
Assuntos
Homeostase/imunologia , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/fisiologia , Interleucinas/fisiologia , Macrófagos/imunologia , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/fisiologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Células Cultivadas , Doença Crônica , Regulação para Baixo/imunologia , Humanos , Imunidade Inata , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/fisiologia , Interleucinas/biossíntese , Ativação de Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Receptores Tipo II do Fator de Necrose Tumoral/antagonistas & inibidores , Líquido Sinovial/imunologia , Líquido Sinovial/metabolismoRESUMO
NADPH oxidase deficiency exacerbates lupus in murine models and patients, but the mechanisms remain unknown. It is hypothesized that NADPH oxidase suppresses autoimmunity by facilitating dead cell clearance via LC3-associated phagocytosis (LAP). The absence of LAP reportedly causes an autoinflammatory syndrome in aged, nonautoimmune mice. Prior work implicated cytochrome b-245, ß polypeptide (CYBB), a component of the NADPH oxidase complex, and the RUN and cysteine-rich domain-containing Beclin 1-interacting protein (RUBICON) as requisite for LAP. To test the hypothesis that NADPH oxidase deficiency exacerbates lupus via a defect in LAP, we deleted Rubicon in the B6.Sle1.Yaa and MRL.Faslpr lupus mouse models. Under this hypothesis, RUBICON deficiency should phenocopy NADPH oxidase deficiency, as both work in the same pathway. However, we observed the opposite - RUBICON deficiency resulted in reduced mortality, renal disease, and autoantibody titers to RNA-associated autoantigens. Given that our data contradict the published role for LAP in autoimmunity, we assessed whether CYBB and RUBICON are requisite for LAP. We found that LAP is not dependent on either of these 2 pathways. To our knowledge, our data reveal RUBICON as a novel regulator of SLE, possibly by a B cell-intrinsic mechanism, but do not support a role for LAP in lupus.
Assuntos
Autofagia , Fagossomos , Idoso , Animais , Modelos Animais de Doenças , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , NADPH Oxidases/metabolismo , FagocitoseRESUMO
Toll-like receptor 9 (TLR9) is a regulator of disease pathogenesis in systemic lupus erythematosus (SLE). Why TLR9 represses disease while TLR7 and MyD88 have the opposite effect remains undefined. To begin to address this question, we created 2 alleles to manipulate TLR9 expression, allowing for either selective deletion or overexpression. We used these to test cell type-specific effects of Tlr9 expression on the regulation of SLE pathogenesis. Notably, Tlr9 deficiency in B cells was sufficient to exacerbate nephritis while extinguishing anti-nucleosome antibodies, whereas Tlr9 deficiency in dendritic cells (DCs), plasmacytoid DCs, and neutrophils had no discernable effect on disease. Thus, B cell-specific Tlr9 deficiency unlinked disease from autoantibody production. Critically, B cell-specific Tlr9 overexpression resulted in ameliorated nephritis, opposite of the effect of deleting Tlr9. Our findings highlight the nonredundant role of B cell-expressed TLR9 in regulating lupus and suggest therapeutic potential in modulating and perhaps even enhancing TLR9 signals in B cells.
Assuntos
Formação de Anticorpos , Autoanticorpos/imunologia , Linfócitos B/imunologia , Regulação da Expressão Gênica/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Transdução de Sinais/imunologia , Receptor Toll-Like 9/imunologia , Animais , Autoanticorpos/genética , Linfócitos B/patologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Modelos Animais de Doenças , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/prevenção & controle , Camundongos , Camundongos Knockout , Transdução de Sinais/genética , Receptor Toll-Like 9/deficiênciaRESUMO
Loss of tolerance to nuclear antigens and multisystem tissue destruction is a hallmark of systemic lupus erythematosus (SLE). Although the source of autoantigen in lupus remains elusive, a compelling hypothetical source is dead cell debris that drives autoimmune activation. Prior reports suggest that neutrophil extracellular traps (NETs) and their associated death pathway, NETosis, are sources of autoantigen in SLE. However, others and we have shown that inhibition of NETs by targeting the NADPH oxidase complex and peptidylarginine deiminase 4 (PADI4) did not ameliorate disease in spontaneous murine models of SLE. Furthermore, myeloperoxidase and PADI4 deletion did not inhibit induced lupus. Since NET formation may occur independently of any one mediator, to address this controversy, we genetically deleted an additional important mediator of NETs and neutrophil effector function, neutrophil elastase (ELANE), in the MRL.Faslpr model of SLE. ELANE deficiency, and by extension ELANE-dependent NETs, had no effect on SLE nephritis, dermatitis, anti-self response, or immune composition in MRL.Faslpr mice. Taken together with prior data from our group and others, these data further challenge the paradigm that NETs and neutrophils are pathogenic in SLE.
Assuntos
Deleção de Genes , Elastase de Leucócito/genética , Lúpus Eritematoso Sistêmico/genética , Animais , Dermatite/genética , Modelos Animais de Doenças , Armadilhas Extracelulares/genética , Feminino , Masculino , Camundongos Endogâmicos C57BL , Nefrite/genéticaRESUMO
Dysregulated proinflammatory cytokine release has been implicated in the pathogenesis of several life-threatening acute lung illnesses such as pneumonia, sepsis, and acute respiratory distress syndrome. Suppressors of cytokine signaling proteins, particularly SOCS2, have recently been described as antiinflammatory mediators. However, the regulation of SOCS2 protein has not been described. Here we describe a mechanism of SOCS2 regulation by the action of the ubiquitin E3 ligase KIAA0317. KIAA0317-mediated degradation of SOCS2 exacerbated inflammation in vitro, and depletion of KIAA0317 in vivo ameliorated pulmonary inflammation. KIAA0317-knockout mice exhibited resistance to LPS-induced pulmonary inflammation, while KIAA03017 reexpression mitigated this effect. We uncovered a small molecule inhibitor of KIAA0317 protein (BC-1365) that prevented SOCS2 degradation and attenuated LPS- and P. aeruginosa-induced lung inflammation in vivo. These studies show KIAA0317 to be a critical mediator of pulmonary inflammation through its degradation of SOCS2 and a potential candidate target for therapeutic inhibition.
Assuntos
Pulmão/metabolismo , Pneumonia/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Adulto , Idoso , Animais , Citocinas/metabolismo , Feminino , Humanos , Imunidade Inata , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Pneumonia/imunologia , Pneumonia/patologia , Ligação Proteica , TranscriptomaRESUMO
Since the discovery and definition of neutrophil extracellular traps (NETs) 14 years ago, numerous characteristics and physiological functions of NETs have been uncovered. Nowadays, the field continues to expand and novel mechanisms that orchestrate formation of NETs, their previously unknown properties, and novel implications in disease continue to emerge. The abundance of available data has also led to some confusion in the NET research community due to contradictory results and divergent scientific concepts, such as pro- and anti-inflammatory roles in pathologic conditions, demarcation from other forms of cell death, or the origin of the DNA that forms the NET scaffold. Here, we present prevailing concepts and state of the science in NET-related research and elaborate on open questions and areas of dispute.
Assuntos
Armadilhas Extracelulares/metabolismo , Neutrófilos/metabolismo , HumanosRESUMO
While T cells are important for the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis, little is known about how T cells function after infiltrating the kidney. The current paradigm suggests that kidney-infiltrating T cells (KITs) are activated effector cells contributing to tissue damage and ultimately organ failure. Herein, we demonstrate that the majority of CD4+ and CD8+ KITs in 3 murine lupus models are not effector cells, as hypothesized, but rather express multiple inhibitory receptors and are highly dysfunctional, with reduced cytokine production and proliferative capacity. In other systems, this hypofunctional profile is linked directly to metabolic and specifically mitochondrial dysfunction, which we also observed in KITs. The T cell phenotype was driven by the expression of an "exhausted" transcriptional signature. Our data thus reveal that the tissue parenchyma has the capability of suppressing T cell responses and limiting damage to self. These findings suggest avenues for the treatment of autoimmunity based on selectively exploiting the exhausted phenotype of tissue-infiltrating T cells.
Assuntos
Autoimunidade , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Nefrite Lúpica , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Rim , Nefrite Lúpica/genética , Nefrite Lúpica/imunologia , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos MRL lpr , Camundongos KnockoutRESUMO
Though recent reports suggest that neutrophil extracellular traps (NETs) are a source of antigenic nucleic acids in systemic lupus erythematosus (SLE), we recently showed that inhibition of NETs by targeting the NADPH oxidase complex via cytochrome b-245, ß polypeptide (cybb) deletion exacerbated disease in the MRL.Faslpr lupus mouse model. While these data challenge the paradigm that NETs promote lupus, it is conceivable that global regulatory properties of cybb and cybb-independent NETs confound these findings. Furthermore, recent reports indicate that inhibitors of peptidyl arginine deiminase, type IV (Padi4), a distal mediator of NET formation, improve lupus in murine models. Here, to clarify the contribution of NETs to SLE, we employed a genetic approach to delete Padi4 in the MRL.Faslpr model and used a pharmacological approach to inhibit PADs in both the anti-glomerular basement membrane model of proliferative nephritis and a human-serum-transfer model of SLE. In contrast to prior inhibitor studies, we found that deletion of Padi4 did not ameliorate any aspect of nephritis, loss of tolerance, or immune activation. Pharmacological inhibition of PAD activity had no effect on end-organ damage in inducible models of glomerulonephritis. These data provide a direct challenge to the concept that NETs promote autoimmunity and target organ injury in SLE.
RESUMO
This article provides an essential curriculum in cervical spine radiology. It discusses the uses of plain radiographs, MR imaging, computed tomography (CT), and CT myelography, in addition to the methodologies of discography, epidural injections under visualization, and facet and nerve root injections. It explains how radiographic images of the cervical spine can differentiate tumors, inflammation, recent or prior trauma, and the range of discal, arthritic, neural, and vascular cervical pathologies and, just as importantly, when they cannot.