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1.
Arterioscler Thromb Vasc Biol ; 44(4): 843-865, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38385286

RESUMO

BACKGROUND: Accumulating evidence implicates the activation of G-protein-coupled PARs (protease-activated receptors) by coagulation proteases in the regulation of innate immune responses. METHODS: Using mouse models with genetic alterations of the PAR2 signaling platform, we have explored contributions of PAR2 signaling to infection with coxsackievirus B3, a single-stranded RNA virus provoking multiorgan tissue damage, including the heart. RESULTS: We show that PAR2 activation sustains correlates of severe morbidity-hemodynamic compromise, aggravated hypothermia, and hypoglycemia-despite intact control of the virus. Following acute viral liver injury, canonical PAR2 signaling impairs the restoration process associated with exaggerated type I IFN (interferon) signatures in response to viral RNA recognition. Metabolic profiling in combination with proteomics of liver tissue shows PAR2-dependent reprogramming of liver metabolism, increased lipid droplet storage, and gluconeogenesis. PAR2-sustained hypodynamic compromise, reprograming of liver metabolism, as well as imbalanced IFN responses are prevented in ß-arrestin coupling-deficient PAR2 C-terminal phosphorylation mutant mice. Thus, wiring between upstream proteases and immune-metabolic responses results from biased PAR2 signaling mediated by intracellular recruitment of ß-arrestin. Importantly, blockade of the TF (tissue factor)-FVIIa (coagulation factor VIIa) complex capable of PAR2 proteolysis with the NAPc2 (nematode anticoagulant protein c2) mitigated virus-triggered pathology, recapitulating effects seen in protease cleavage-resistant PAR2 mice. CONCLUSIONS: These data provide insights into a TF-FVIIa signaling axis through PAR2-ß-arrestin coupling that is a regulator of inflammation-triggered tissue repair and hemodynamic compromise in coxsackievirus B3 infection and can potentially be targeted with selective coagulation inhibitors.


Assuntos
Insuficiência de Múltiplos Órgãos , Tromboplastina , Animais , Camundongos , Tromboplastina/metabolismo , beta-Arrestinas/metabolismo , Receptor PAR-2/genética , Fator VIIa/metabolismo , Endopeptidases/metabolismo
2.
Z Rheumatol ; 83(1): 4-14, 2024 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-37921883

RESUMO

Monogenic mutations in laccase domain-containing 1 (LACC1) are associated with clinical pictures that mimic severe courses of polyarticular or systemic juvenile idiopathic arthritis. The diseases are characterized by an early onset during the first year of life, a familial clustering and a high inflammatory activity. The courses are mostly difficult to influence and often lead to sequelae. In this article four cases from two families are presented in which the homozygous mutation p.T276fs* in LACC1 was detected. The children initially suffered from polyarticular or systemic forms of juvenile arthritis. Of the patients two are currently being treated with tocilizumab and methotrexate and one female patient without a basis treatment is currently only receiving local repeated intra-articular steroids. A fourth female patient underwent an allogeneic bone marrow transplantation due to a relapse of an acute lymphatic leukemia. Since then, no further inflammatory symptoms have occurred. The cases presented are compared with the other 50 courses published to date. In addition, recent studies investigating the influence of LACC1 mutations, particularly on macrophage function, are summarized.


Assuntos
Artrite Juvenil , Criança , Humanos , Feminino , Artrite Juvenil/diagnóstico , Artrite Juvenil/genética , Artrite Juvenil/complicações , Lacase/genética , Lacase/uso terapêutico , Metotrexato/uso terapêutico , Mutação/genética , Homozigoto , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/uso terapêutico
3.
Circulation ; 141(23): 1885-1902, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32160764

RESUMO

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy is often accompanied by immune-related pathology, with an increasing occurrence of high-risk ICI-related myocarditis. Understanding the mechanisms involved in this side effect could enable the development of management strategies. In mouse models, immune checkpoints, such as PD-1 (programmed cell death protein 1), control the threshold of self-antigen responses directed against cardiac TnI (troponin I). We aimed to identify how the immunoproteasome, the main proteolytic machinery in immune cells harboring 3 distinct protease activities in the LMP2 (low-molecular-weight protein 2), LMP7 (low-molecular-weight protein 7), and MECL1 (multicatalytic endopeptidase complex subunit 1) subunit, affects TnI-directed autoimmune pathology of the heart. METHODS: TnI-directed autoimmune myocarditis (TnI-AM), a CD4+ T-cell-mediated disease, was induced in mice lacking all 3 immunoproteasome subunits (triple-ip-/-) or lacking either the gene encoding LMP2 and LMP7 by immunization with a cardiac TnI peptide. Alternatively, before induction of TnI-AM or after establishment of autoimmune myocarditis, mice were treated with the immunoproteasome inhibitor ONX 0914. Immune parameters defining heart-specific autoimmunity were investigated in experimental TnI-AM and in 2 cases of ICI-related myocarditis. RESULTS: All immunoproteasome-deficient strains showed mitigated autoimmune-related cardiac pathology with less inflammation, lower proinflammatory and chemotactic cytokines, less interleukin-17 production, and reduced fibrosis formation. Protection from TnI-directed autoimmune heart pathology with improved cardiac function in LMP7-/- mice involved a changed balance between effector and regulatory CD4+ T cells in the spleen, with CD4+ T cells from LMP7-/- mice showing a higher expression of inhibitory PD-1 molecules. Blocked immunoproteasome proteolysis, by treatment of TLR2 (Toll-like receptor 2)-engaged and TLR7 (Toll-like receptor 7)/TLR8 (Toll-like receptor 8)-engaged CD14+ monocytes with ONX 0914, diminished proinflammatory cytokine responses, thereby reducing the boost for the expansion of self-reactive CD4+ T cells. Correspondingly, in mice, ONX 0914 treatment reversed cardiac autoimmune pathology, preventing the induction and progression of TnI-AM when self-reactive CD4+ T cells were primed. The autoimmune signature during experimental TnI-AM, with high immunoproteasome expression, immunoglobulin G deposition, interleukin-17 production in heart tissue, and TnI-directed humoral autoimmune responses, was also present in 2 cases of ICI-related myocarditis, demonstrating the activation of heart-specific autoimmune reactions by ICI therapy. CONCLUSIONS: By reversing heart-specific autoimmune responses, immunoproteasome inhibitors applied to a mouse model demonstrate their potential to aid in the management of autoimmune myocarditis in humans, possibly including patients with ICI-related heart-specific autoimmunity.


Assuntos
Doenças Autoimunes/imunologia , Modelos Animais de Doenças , Deleção de Genes , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunidade/imunologia , Miocardite/imunologia , Complexo de Endopeptidases do Proteassoma/imunologia , Idoso , Sequência de Aminoácidos , Animais , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/genética , Cisteína Endopeptidases/deficiência , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/imunologia , Feminino , Humanos , Imunidade/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Miocardite/induzido quimicamente , Miocardite/genética , Complexo de Endopeptidases do Proteassoma/deficiência , Complexo de Endopeptidases do Proteassoma/genética
4.
Basic Res Cardiol ; 116(1): 7, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33523326

RESUMO

A preclinical model of troponin I-induced myocarditis (AM) revealed a prominent role of the immunoproteasome (ip), the main immune cell-resident proteasome isoform, in heart-directed autoimmunity. Viral infection of the heart is a known trigger of cardiac autoimmunity, with the ip enhancing systemic inflammatory responses after infection with a cardiotropic coxsackievirusB3 (CV). Here, we used ip-deficient A/J-LMP7-/- mice to investigate the role of ip-mediated effects on adaptive immunity in CV-triggered myocarditis and found no alteration of the inflammatory heart tissue damage or cardiac function in comparison to wild-type controls. Aiming to define the impact of the systemic inflammatory storm under the control of ip proteolysis during CV infection, we targeted the ip in A/J mice with the inhibitor ONX 0914 after the first cycle of infection, when systemic inflammation has set in, well before cardiac inflammation. During established acute myocarditis, the ONX 0914 treatment group had the same reduction in cardiac output as the controls, with inflammatory responses in heart tissue being unaffected by the compound. Based on these findings and with regard to the known anti-inflammatory role of ONX 0914 in CV infection, we conclude that the efficacy of ip inhibitors for CV-triggered myocarditis in A/J mice relies on their immunomodulatory effects on the systemic inflammatory reaction.


Assuntos
Anti-Inflamatórios/farmacologia , Infecções por Coxsackievirus/tratamento farmacológico , Inflamação/tratamento farmacológico , Células Mieloides/efeitos dos fármacos , Miocardite/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Oligopeptídeos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Animais , Células Cultivadas , Infecções por Coxsackievirus/enzimologia , Infecções por Coxsackievirus/imunologia , Modelos Animais de Doenças , Enterovirus Humano B/imunologia , Enterovirus Humano B/patogenicidade , Interações Hospedeiro-Patógeno , Inflamação/enzimologia , Inflamação/imunologia , Inflamação/virologia , Masculino , Camundongos Knockout , Células Mieloides/enzimologia , Células Mieloides/imunologia , Células Mieloides/virologia , Miocardite/enzimologia , Miocardite/imunologia , Miocardite/virologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/virologia , Complexo de Endopeptidases do Proteassoma/genética , Proteólise
6.
Sci Immunol ; 9(92): eadi9769, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38207055

RESUMO

UNC93B1 is critical for trafficking and function of nucleic acid-sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self-nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype-specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.


Assuntos
Lúpus Eritematoso Sistêmico , Receptor 7 Toll-Like , Camundongos , Animais , Humanos , Receptor 7 Toll-Like/genética , Autoimunidade/genética , Receptor Toll-Like 9/metabolismo , Receptor 8 Toll-Like , Receptor 3 Toll-Like/metabolismo , Lúpus Eritematoso Sistêmico/genética , Proteínas de Membrana Transportadoras
7.
J Clin Med ; 10(8)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33923887

RESUMO

The ubiquitin-proteasome system (UPS) is involved in multiple cellular functions including the regulation of protein homeostasis, major histocompatibility (MHC) class I antigen processing, cell cycle proliferation and signaling. In humans, proteasome loss-of-function mutations result in autoinflammation dominated by a prominent type I interferon (IFN) gene signature. These genomic alterations typically cause the development of proteasome-associated autoinflammatory syndromes (PRAAS) by impairing proteasome activity and perturbing protein homeostasis. However, an abnormal increased proteasomal activity can also be found in other human inflammatory diseases. In this review, we cast a light on the different clinical aspects of proteasomal activity in human disease and summarize the currently studied therapeutic approaches.

8.
J Clin Med ; 10(4)2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673234

RESUMO

Adult-onset Still's disease (AoSD) is a rare systemic autoinflammatory disease characterized by arthritis, spiking fever, skin rash and elevated ferritin levels. The reason behind the nomenclature of this condition is that AoSD shares certain symptoms with Still's disease in children, currently named systemic-onset juvenile idiopathic arthritis. Immune dysregulation plays a central role in AoSD and is characterized by pathogenic involvement of both arms of the immune system. Furthermore, the past two decades have seen a large body of immunological research on cytokines, which has attributed to both a better understanding of AoSD and revolutionary advances in treatment. Additionally, recent studies have introduced a new approach by grouping patients with AoSD into only two phenotypes: one with predominantly systemic features and one with a chronic articular disease course. Diagnosis presupposes an extensive diagnostic workup to rule out infections and malignancies. The severe end of the spectrum of this disease is secondary haemophagocytic lymphohistiocytosis, better known as macrophage activation syndrome. In this review, we discuss current research conducted on the pathogenesis, diagnosis, classification, biomarkers and complications of AoSD, as well as the treatment strategy at each stage of the disease course. We also highlight the similarities and differences between AoSD and systemic-onset juvenile idiopathic arthritis. There is a considerable need for large multicentric prospective trials.

9.
EMBO Mol Med ; 10(2): 200-218, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29295868

RESUMO

Severe heart pathology upon virus infection is closely associated with the immunological equipment of the host. Since there is no specific treatment available, current research focuses on identifying new drug targets to positively modulate predisposing immune factors. Utilizing a murine model with high susceptibility to coxsackievirus B3-induced myocarditis, this study describes ONX 0914-an immunoproteasome-specific inhibitor-as highly protective during severe heart disease. Represented by reduced heart infiltration of monocytes/macrophages and diminished organ damage, ONX 0914 treatment reversed fulminant pathology. Virus-induced immune response features like overwhelming pro-inflammatory cytokine and chemokine production as well as a progressive loss of lymphocytes all being reminiscent of a sepsis-like disease course were prevented by ONX 0914. Although the viral burden was only minimally affected in highly susceptible mice, resulting maintenance of immune homeostasis improved the cardiac output, and saved animals from severe illness as well as high mortality. Altogether, this could make ONX 0914 a potent drug for the treatment of severe virus-mediated inflammation of the heart and might rank immunoproteasome inhibitors among drugs for preventing pathogen-induced immunopathology.


Assuntos
Infecções por Coxsackievirus/imunologia , Enterovirus/efeitos dos fármacos , Miocardite/tratamento farmacológico , Miocardite/virologia , Oligopeptídeos/farmacologia , Inibidores de Proteassoma/farmacologia , Animais , Débito Cardíaco , Células Cultivadas , Infecções por Coxsackievirus/tratamento farmacológico , Memória Imunológica , Camundongos , Modelos Animais , Miocardite/imunologia , Oligopeptídeos/imunologia , Oligopeptídeos/uso terapêutico , Inibidores de Proteassoma/imunologia , Inibidores de Proteassoma/uso terapêutico
10.
Front Immunol ; 9: 2303, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30349538

RESUMO

Myocarditis is an inflammatory disease of the heart muscle most commonly caused by viral infection and often maintained by autoimmunity. Virus-induced tissue damage triggers chemokine production and, subsequently, immune cell infiltration with pro-inflammatory and pro-fibrotic cytokine production follows. In patients, the overall inflammatory burden determines the disease outcome. Following the aim to define specific molecules that drive both immunopathology and/or autoimmunity in inflammatory heart disease, here we report on increased expression of colony stimulating factor 1 (CSF-1) in patients with myocarditis. CSF-1 controls monocytes originating from hematopoietic stem cells and subsequent progenitor stages. Both, monocytes and macrophages are centrally involved in mediating tissue damage and fibrotic scarring in the heart. CSF-1 influences monocytes via engagement of CSF-1 receptor, and it is also produced by cells of the mononuclear phagocyte system themselves. Based on this, we sought to modulate the virus-triggered inflammatory response in an experimental model of Coxsackievirus B3-induced myocarditis by silencing the CSF-1 axis in myeloid cells using nanoparticle-encapsulated siRNA. siCSF-1 inverted virus-mediated immunopathology as reflected by lower troponin T levels, a reduction of accumulating myeloid cells in heart tissue and improved cardiac function. Importantly, pathogen control was maintained and the virus was efficiently cleared from heart tissue. Since viral heart disease triggers heart-directed autoimmunity, in a second approach we investigated the influence of CSF-1 upon manifestation of heart tissue inflammation during experimental autoimmune myocarditis (EAM). EAM was induced in Balb/c mice by immunization with a myocarditogenic myosin-heavy chain-derived peptide dissolved in complete Freund's adjuvant. siCSF-1 treatment initiated upon established disease inhibited monocyte infiltration into heart tissue and this suppressed cardiac injury as reflected by diminished cardiac fibrosis and improved cardiac function at later states. Mechanistically, we found that suppression of CSF-1 production arrested both differentiation and maturation of monocytes and their precursors in the bone marrow. In conclusion, during viral and autoimmune myocarditis silencing of the myeloid CSF-1 axis by nanoparticle-encapsulated siRNA is beneficial for preventing inflammatory tissue damage in the heart and preserving cardiac function without compromising innate immunity's critical defense mechanisms.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Infecções por Coxsackievirus/tratamento farmacológico , Enterovirus Humano B , Fator Estimulador de Colônias de Macrófagos/genética , Miocardite/tratamento farmacológico , RNA Interferente Pequeno/uso terapêutico , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Infecções por Coxsackievirus/genética , Infecções por Coxsackievirus/patologia , Modelos Animais de Doenças , Regulação para Baixo , Inativação Gênica , Humanos , Inflamação/prevenção & controle , Masculino , Camundongos Endogâmicos BALB C , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Miocardite/genética , Miocardite/patologia , Miocardite/virologia , Miocárdio/metabolismo , Miocárdio/patologia , Nanopartículas , RNA Interferente Pequeno/administração & dosagem
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