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1.
Immunity ; 45(1): 46-59, 2016 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-27396959

RESUMO

Macrophages are a crucial component of the innate immune system in sensing pathogens and promoting local and systemic inflammation. RIPK1 and RIPK3 are homologous kinases, previously linked to activation of necroptotic death. In this study, we have described roles for these kinases as master regulators of pro-inflammatory gene expression induced by lipopolysaccharide, independent of their well-documented cell death functions. In primary macrophages, this regulation was elicited in the absence of caspase-8 activity, required the adaptor molecule TRIF, and proceeded in a cell autonomous manner. RIPK1 and RIPK3 kinases promoted sustained activation of Erk, cFos, and NF-κB, which were required for inflammatory changes. Utilizing genetic and pharmacologic tools, we showed that RIPK1 and RIPK3 account for acute inflammatory responses induced by lipopolysaccharide in vivo; notably, this regulation did not require exogenous manipulation of caspases. These findings identified a new pharmacologically accessible pathway that may be relevant to inflammatory pathologies.


Assuntos
Imunidade Inata , Inflamação/imunologia , Macrófagos/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Caspase 8/genética , Caspase 8/metabolismo , Células Cultivadas , Feminino , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necrose , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais , Transcriptoma
2.
J Immunol ; 198(11): 4435-4447, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28461567

RESUMO

The innate immune response is a central element of the initial defense against bacterial and viral pathogens. Macrophages are key innate immune cells that upon encountering pathogen-associated molecular patterns respond by producing cytokines, including IFN-ß. In this study, we identify a novel role for RIPK1 and RIPK3, a pair of homologous serine/threonine kinases previously implicated in the regulation of necroptosis and pathologic tissue injury, in directing IFN-ß production in macrophages. Using genetic and pharmacologic tools, we show that catalytic activity of RIPK1 directs IFN-ß synthesis induced by LPS in mice. Additionally, we report that RIPK1 kinase-dependent IFN-ß production may be elicited in an analogous fashion using LPS in bone marrow-derived macrophages upon inhibition of caspases. Notably, this regulation requires kinase activities of both RIPK1 and RIPK3, but not the necroptosis effector protein, MLKL. Mechanistically, we provide evidence that necrosome-like RIPK1 and RIPK3 aggregates facilitate canonical TRIF-dependent IFN-ß production downstream of the LPS receptor TLR4. Intriguingly, we also show that RIPK1 and RIPK3 kinase-dependent synthesis of IFN-ß is markedly induced by avirulent strains of Gram-negative bacteria, Yersinia and Klebsiella, and less so by their wild-type counterparts. Overall, these observations identify unexpected roles for RIPK1 and RIPK3 kinases in the production of IFN-ß during the host inflammatory responses to bacterial infection and suggest that the axis in which these kinases operate may represent a target for bacterial virulence factors.


Assuntos
Interferon beta/biossíntese , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Apoptose/imunologia , Bactérias Gram-Negativas/imunologia , Interferon beta/imunologia , Klebsiella/imunologia , Macrófagos/microbiologia , Camundongos , Necrose/imunologia , Fosforilação , Receptor 4 Toll-Like/imunologia , Yersinia/imunologia
3.
Curr Top Microbiol Immunol ; 403: 37-75, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-26385769

RESUMO

Receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3 ) are homologous serine-threonine kinases that were recognized for their roles in directing programmed necrotic cell death or necroptosis under a broad range of pathologic settings. Emerging evidence suggests new physiologic roles for RIPK1 and RIPK3 in mediating cell death of innate immune responses. Our review discusses current evidence on the mechanisms and the impact of RIPK1- and/or RIPK3-dependent cell death in responses to a variety of viral and bacterial pathogens. Furthermore, the discussion also summarizes emerging roles for RIPK1 and RIPK3 in other facets of host immunity, including the maintenance of epithelial barrier function and pro-inflammatory processes that may, in some cases, manifest independent of cell death. Finally, we briefly consider the therapeutic opportunities in targeting RIPK1- and RIPK3-dependent processes in infection and immunity.


Assuntos
Morte Celular/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Animais , Humanos
4.
J Cardiovasc Dev Dis ; 11(4)2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38667722

RESUMO

BACKGROUND: This study aims to understand and describe the clinical impact of SARS-CoV-2 (COVID-19) infection in patients with Hypertrophic Cardiomyopathy (HCM). METHODS: A data repository of over 6.6 million patients in a large metropolitan (Chicago IL) healthcare system was queried to identify adults with a history of HCM and COVID-19 infection between 2019 and 2021. Propensity score-matched analysis was performed based on age, sex, BMI, and elements of the cardiovascular history, including tobacco use, hypertension, hyperlipidemia, myocardial injury, and heart failure. RESULTS: Individuals with HCM and COVID-19 infection had more total hospitalizations (41.6 v 23 per 100 persons, p < 0.01), more heart-failure-related hospitalizations (24.2 v 8.7 per 100-persons, p < 0.01), more non-ST elevation myocardial injury (NSTEMI) hospitalizations (8.6 v 4.6 per 100-persons, p < 0.01), and increased mortality (10.8 v 5 per 100-persons, p < 0.01) compared to HCM patients without a history of COVID-19 infection. Patients with HCM and COVID-19 were also noted to have a higher peak CRP when compared to those without prior COVID-19 (Inter-quartile range of 9.0-106.9 v 1.8-21.3, p < 0.01). CONCLUSIONS: In patients with HCM, COVID-19 infection is associated with increased incidence of myocardial injury, increased number of total and heart-failure specific hospitalizations, and increased mortality.

5.
Biomolecules ; 13(10)2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37892217

RESUMO

The field of cardio-immunology has emerged from discoveries that define roles for innate and adaptive immune responses associated with myocardial inflammation and heart failure. Dendritic cells (DCs) comprise an important cellular compartment that contributes to systemic immune surveillance at the junction of innate and adaptive immunity. Once described as a singular immune subset, we now appreciate that DCs consist of a heterogeneous pool of subpopulations, each with distinct effector functions that can uniquely regulate the acute and chronic inflammatory response. Nevertheless, the cardiovascular-specific context involving DCs in negotiating the biological response to myocardial injury is not well understood. Herein, we review our current understanding of the role of DCs in cardiac inflammation and heart failure, including gaps in knowledge and clinical relevance.


Assuntos
Insuficiência Cardíaca , Miocardite , Humanos , Inflamação , Imunidade Adaptativa , Células Dendríticas
6.
Clin Case Rep ; 11(11): e8052, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37927980

RESUMO

We present a case of a quadriplegic male who developed ventricular fibrillation associated with an anomalous aortic origin of the right coronary artery. Successful revascularization was achieved with percutaneous coronary intervention. This case highlights the application of an unconventional approach to resolve ischemia in a patient with prohibitive surgical risk.

7.
Ophthalmol Glaucoma ; 2(3): 167-171, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32672586

RESUMO

PURPOSE: To investigate the long-term effectiveness of intraocular pressure (IOP) and medication reduction in patients who have undergone micropulse transscleral cyclophotocoagulation (mTS-CPC). DESIGN: Retrospective chart review. PARTICIPANTS: A total of 73 eyes of 62 patients treated no more than 1 time with mTS-CPC in a practice in New York City with at least 1 year of follow-up. METHODS: Treatment was 100 seconds of mTS-CPC with energy titrated on the basis of visual acuity. Paired t test and multivariable analysis were performed with SAS (SAS Institute Inc, Cary, NC). MAIN OUTCOME MEASURES: Visual acuity, IOP, medication burden, phthisis, and development of macular edema were followed. RESULTS: Average initial IOP was 25.5±9.4, and average number of initial medications was 3.1±1.1. At 1 year, average IOP was 13.8±7.0 (46% reduction) and average number of medications was 2.5±1.0 (19% reduction). A total of 11 of 15 patients (73.3%) initially taking an oral carbonic anhydrase inhibitor before CPC did not require the oral carbonic anhydrase inhibitor 1 year after treatment. Seventy-six percent of patients obtained at least 20% IOP reduction. Multivariate analysis found IOP reduction was associated with power used and preoperative IOP, whereas medication reduction was associated with initial medication burden. Notably, there was a 57% reduction in IOP at 2500 mW power and a 30% reduction at 2000 mW power. No patients developed macular edema or phthisis from the procedure. Some 18.8% of patients with 20/400 vision or better experienced persistent vision loss of ≥2 lines after the procedure, and 10% of patients with light perception to count finger vision progressed to no light perception (NLP) after the procedure. Of patients with 20/400 vision or better, 12.5% gained ≥2 lines of visual acuity on the Snellen chart at the postoperative year 1 visit. In addition, 15.4% of patients with count fingers to NLP vision improved at the postoperative year 1 visit after treatment. One of 6 patients (16.7%) with NLP gained vision at the postoperative year 1 visit. CONCLUSIONS: This study provides evidence that mTS-CPC is a clinically useful procedure associated with good long-term medication burden reduction and IOP reduction that follows a dose-response pattern related to power used.


Assuntos
Corpo Ciliar/cirurgia , Glaucoma de Ângulo Aberto/cirurgia , Pressão Intraocular/fisiologia , Fotocoagulação a Laser/métodos , Esclera/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo
8.
Methods Mol Biol ; 1857: 19-33, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30136227

RESUMO

Necroptosis is mediated by the formation of the detergent-insoluble necrosome complex between Ser/Thr kinases RIPK1 and RIPK3, which mediates RIPK3-dependent phosphorylation and activation of the critical necroptosis effector MLKL. Small molecule screens have been instrumental in the development of new chemical probes for this pathway. In this chapter, we describe several cellular assays that are readily amendable for the identification of new modulators of necroptosis as well as secondary assays to facilitate initial characterization of the mode of activity of small molecule hits.


Assuntos
Apoptose , Técnicas de Química Combinatória/métodos , Necrose , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Humanos , Bibliotecas de Moléculas Pequenas/isolamento & purificação
10.
Cell Death Dis ; 9(3): 359, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29500402

RESUMO

Receptor-interacting protein kinases 1 and 3 (RIPK1/3) have best been described for their role in mediating a regulated form of necrosis, referred to as necroptosis. During this process, RIPK3 phosphorylates mixed lineage kinase domain-like (MLKL) to cause plasma membrane rupture. RIPK3-deficient mice have recently been demonstrated to be protected in a series of disease models, but direct evidence for activation of necroptosis in vivo is still limited. Here, we sought to further examine the activation of necroptosis in kidney ischemia-reperfusion injury (IRI) and from TNFα-induced severe inflammatory response syndrome (SIRS), two models of RIPK3-dependent injury. In both models, MLKL-ko mice were significantly protected from injury to a degree that was slightly, but statistically significantly exceeding that of RIPK3-deficient mice. We also demonstrated, for the first time, accumulation of pMLKL in the necrotic tubules of human patients with acute kidney injury. However, our data also uncovered unexpected elevation of blood flow in MLKL-ko animals, which may be relevant to IRI and should be considered in the future. To further understand the mode of regulation of cell death by MLKL, we screened a panel of clinical plasma membrane channel blockers and we found phenytoin to inhibit necroptosis. However, we further found that phenytoin attenuated RIPK1 kinase activity in vitro, likely due to the hydantoin scaffold also present in necrostatin-1, and blocked upstream necrosome formation steps in the cells undergoing necroptosis. We further report that this clinically used anti-convulsant drug displayed protection from kidney IRI and TNFα-induces SIRS in vivo. Overall, our data reveal the relevance of RIPK3-pMLKL regulation for acute kidney injury and identifies an FDA-approved drug that may be useful for immediate clinical evaluation of inhibition of pro-death RIPK1/RIPK3 activities in human diseases.


Assuntos
Anticonvulsivantes/farmacologia , Necrose/prevenção & controle , Fenitoína/farmacologia , Injúria Renal Aguda/patologia , Animais , Biópsia , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Células HT29 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necrose/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Síndrome de Resposta Inflamatória Sistêmica/induzido quimicamente , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Fator de Necrose Tumoral alfa/farmacologia
12.
Trends Pharmacol Sci ; 38(3): 202-225, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28126382

RESUMO

A process of regulated necrosis, termed necroptosis, has been recognized as a major contributor to cell death and inflammation occurring under a wide range of pathologic settings. The core event in necroptosis is the formation of the detergent-insoluble 'necrosome' complex of homologous Ser/Thr kinases, receptor protein interacting kinase 1 (RIPK1) and receptor interacting protein kinase 3 (RIPK3), which promotes phosphorylation of a key prodeath effector, mixed lineage kinase domain-like (MLKL), by RIPK3. Core necroptosis mediators are under multiple controls, which have been a subject of intense investigation. Additional, non-necroptotic functions of these factors, primarily in controlling apoptosis and inflammatory responses, have also begun to emerge. This review will provide an overview of the current understanding of the human disease relevance of this pathway, and potential therapeutic strategies, targeting necroptosis mediators in various pathologies.


Assuntos
Necrose/enzimologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Humanos
14.
Chem Biol ; 22(9): 1174-84, 2015 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-26320862

RESUMO

RIPK2 mediates pro-inflammatory signaling from the bacterial sensors NOD1 and NOD2, and is an emerging therapeutic target in autoimmune and inflammatory diseases. We observed that cellular RIPK2 can be potently inhibited by type II inhibitors that displace the kinase activation segment, whereas ATP-competitive type I inhibition was only poorly effective. The most potent RIPK2 inhibitors were the US Food and Drug Administration-approved drugs ponatinib and regorafenib. Their mechanism of action was independent of NOD2 interaction and involved loss of downstream kinase activation as evidenced by lack of RIPK2 autophosphorylation. Notably, these molecules also blocked RIPK2 ubiquitination and, consequently, inflammatory nuclear factor κB signaling. In monocytes, the inhibitors selectively blocked NOD-dependent tumor necrosis factor production without affecting lipopolysaccharide-dependent pathways. We also determined the first crystal structure of RIPK2 bound to ponatinib, and identified an allosteric site for inhibitor development. These results highlight the potential for type II inhibitors to treat indications of RIPK2 activation as well as inflammation-associated cancers.


Assuntos
Proteína Adaptadora de Sinalização NOD1/antagonistas & inibidores , Proteína Adaptadora de Sinalização NOD2/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Células Cultivadas , Humanos , Imidazóis/química , Imidazóis/farmacologia , Inflamação/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/química , Piridazinas/química , Piridazinas/farmacologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Células Sf9 , Transdução de Sinais/efeitos dos fármacos , Ubiquitinação/efeitos dos fármacos
15.
Cell Rep ; 10(11): 1850-60, 2015 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-25801024

RESUMO

RIPK1 and RIPK3, two closely related RIPK family members, have emerged as important regulators of pathologic cell death and inflammation. In the current work, we report that the Bcr-Abl inhibitor and anti-leukemia agent ponatinib is also a first-in-class dual inhibitor of RIPK1 and RIPK3. Ponatinib potently inhibited multiple paradigms of RIPK1- and RIPK3-dependent cell death and inflammatory tumor necrosis factor alpha (TNF-α) gene transcription. We further describe design strategies that utilize the ponatinib scaffold to develop two classes of inhibitors (CS and PN series), each with greatly improved selectivity for RIPK1. In particular, we detail the development of PN10, a highly potent and selective "hybrid" RIPK1 inhibitor, capturing the best properties of two different allosteric RIPK1 inhibitors, ponatinib and necrostatin-1. Finally, we show that RIPK1 inhibitors from both classes are powerful blockers of TNF-induced injury in vivo. Altogether, these findings outline promising candidate molecules and design approaches for targeting RIPK1- and RIPK3-driven inflammatory pathologies.


Assuntos
Antineoplásicos/farmacologia , Imidazóis/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/farmacologia , Proteína Serina-Treonina Quinases de Interação com Receptores/química , Sequência de Aminoácidos , Animais , Antineoplásicos/química , Feminino , Células HEK293 , Humanos , Imidazóis/química , Células Jurkat , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Piridazinas/química , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Especificidade por Substrato
16.
Cell Metab ; 14(4): 516-27, 2011 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-21982711

RESUMO

Under conditions of obesity and insulin resistance, the serine/threonine protein kinase Akt/PKB is required for lipid accumulation in liver. Two forkhead transcription factors, FoxA2 and FoxO1, have been suggested to function downstream of and to be negatively regulated by Akt and are proposed as key determinants of hepatic triglyceride content. In this study, we utilize genetic loss of function experiments to show that constitutive activation of neither FoxA2 nor FoxO1 can account for the protection from steatosis afforded by deletion of Akt2 in liver. Rather, another downstream target positively regulated by Akt, the mTORC1 complex, is required in vivo for de novo lipogenesis and Srebp1c expression. Nonetheless, activation of mTORC1 and SREBP1c is not sufficient to drive postprandial lipogenesis in the absence of Akt2. These data show that insulin signaling through Akt2 promotes anabolic lipid metabolism independent of Foxa2 or FoxO1 and through pathways additional to the mTORC1-dependent activation of SREBP1c.


Assuntos
Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Animais , Antirreumáticos/farmacologia , Aurotioglucose/farmacologia , Dieta Hiperlipídica , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/deficiência , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Fator 3-beta Nuclear de Hepatócito/metabolismo , Insulina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Knockout , Complexos Multiproteicos , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/deficiência , Proteínas Proto-Oncogênicas c-akt/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Serina-Treonina Quinases TOR , Triglicerídeos/metabolismo
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