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1.
Annu Rev Immunol ; 33: 49-77, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25493334

RESUMEN

Induction, production, and release of proinflammatory cytokines are essential steps to establish an effective host defense. Cytokines of the interleukin-1 (IL-1) family induce inflammation and regulate T lymphocyte responses while also displaying homeostatic and metabolic activities. With the exception of the IL-1 receptor antagonist, all IL-1 family cytokines lack a signal peptide and require proteolytic processing into an active molecule. One such unique protease is caspase-1, which is activated by protein platforms called the inflammasomes. However, increasing evidence suggests that inflammasomes and caspase-1 are not the only mechanism for processing IL-1 cytokines. IL-1 cytokines are often released as precursors and require extracellular processing for activity. Here we review the inflammasome-independent enzymatic processes that are able to activate IL-1 cytokines, paying special attention to neutrophil-derived serine proteases, which subsequently induce inflammation and modulate host defense. The inflammasome-independent processing of IL-1 cytokines has important consequences for understanding inflammatory diseases, and it impacts the design of IL-1-based modulatory therapies.


Asunto(s)
Citocinas/metabolismo , Inflamasomas/metabolismo , Interleucina-1/metabolismo , Animales , Susceptibilidad a Enfermedades , Humanos , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo
2.
Nat Immunol ; 20(9): 1138-1149, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31427775

RESUMEN

Interleukin (IL)-1R3 is the co-receptor in three signaling pathways that involve six cytokines of the IL-1 family (IL-1α, IL-1ß, IL-33, IL-36α, IL-36ß and IL-36γ). In many diseases, multiple cytokines contribute to disease pathogenesis. For example, in asthma, both IL-33 and IL-1 are of major importance, as are IL-36 and IL-1 in psoriasis. We developed a blocking monoclonal antibody (mAb) to human IL-1R3 (MAB-hR3) and demonstrate here that this antibody specifically inhibits signaling via IL-1, IL-33 and IL-36 in vitro. Also, in three distinct in vivo models of disease (crystal-induced peritonitis, allergic airway inflammation and psoriasis), we found that targeting IL-1R3 with a single mAb to mouse IL-1R3 (MAB-mR3) significantly attenuated heterogeneous cytokine-driven inflammation and disease severity. We conclude that in diseases driven by multiple cytokines, a single antagonistic agent such as a mAb to IL-1R3 is a therapeutic option with considerable translational benefit.


Asunto(s)
Anticuerpos Bloqueadores/farmacología , Anticuerpos Monoclonales/farmacología , Proteína Accesoria del Receptor de Interleucina-1/antagonistas & inhibidores , Peritonitis/inmunología , Neumonía/inmunología , Psoriasis/inmunología , Células A549 , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Imiquimod/toxicidad , Inflamación/patología , Interleucina-1/inmunología , Proteína Accesoria del Receptor de Interleucina-1/inmunología , Interleucina-1beta/inmunología , Interleucina-33/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ovalbúmina/toxicidad , Peritonitis/tratamiento farmacológico , Peritonitis/patología , Neumonía/tratamiento farmacológico , Neumonía/patología , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Transducción de Señal/inmunología , Ácido Úrico/toxicidad
4.
Cell ; 167(4): 1111-1124.e13, 2016 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-27814508

RESUMEN

Differences in susceptibility to immune-mediated diseases are determined by variability in immune responses. In three studies within the Human Functional Genomics Project, we assessed the effect of environmental and non-genetic host factors of the genetic make-up of the host and of the intestinal microbiome on the cytokine responses in humans. We analyzed the association of these factors with circulating mediators and with six cytokines after stimulation with 19 bacterial, fungal, viral, and non-microbial metabolic stimuli in 534 healthy subjects. In this first study, we show a strong impact of non-genetic host factors (e.g., age and gender) on cytokine production and circulating mediators. Additionally, annual seasonality is found to be an important environmental factor influencing cytokine production. Alpha-1-antitrypsin concentrations partially mediate the seasonality of cytokine responses, whereas the effect of vitamin D levels is limited. The complete dataset has been made publicly available as a comprehensive resource for future studies. PAPERCLIP.


Asunto(s)
Citocinas/genética , Citocinas/inmunología , Interacción Gen-Ambiente , Adolescente , Adulto , Anciano , Envejecimiento , Animales , Artritis/inmunología , Sangre/inmunología , Índice de Masa Corporal , Femenino , Proyecto Genoma Humano , Humanos , Infecciones/inmunología , Infecciones/microbiología , Infecciones/virología , Inflamación/inmunología , Inflamación/microbiología , Leucocitos Mononucleares/inmunología , Macrófagos/inmunología , Masculino , Ratones , Persona de Mediana Edad , Estaciones del Año , Caracteres Sexuales
5.
Nat Immunol ; 18(8): 826-831, 2017 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-28722720

RESUMEN

Biologists, physicians and immunologists have contributed to the understanding of the cellular participants and biological pathways involved in inflammation. Here, we provide a general guide to the cellular and humoral contributors to inflammation as well as to the pathways that characterize inflammation in specific organs and tissues.


Asunto(s)
Enfermedades Transmisibles/inmunología , Inmunidad Celular/inmunología , Inmunidad Humoral/inmunología , Inflamación/inmunología , Enfermedad Aguda , Enfermedad Crónica , Humanos
7.
Immunity ; 50(4): 778-795, 2019 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-30995499

RESUMEN

Forty years after its naming, interleukin-1 (IL-1) is experiencing a renaissance brought on by the growing understanding of its context-dependent roles and advances in the clinic. Recent studies have identified important roles for members of the IL-1 family-IL-18, IL-33, IL-36, IL-37, and IL-38-in inflammation and immunity. Here, we review the complex functions of IL-1 family members in the orchestration of innate and adaptive immune responses and their diversity and plasticity. We discuss the varied roles of IL-1 family members in immune homeostasis and their contribution to pathologies, including autoimmunity and auto-inflammation, dysmetabolism, cardiovascular disorders, and cancer. The trans-disease therapeutic activity of anti-IL-1 strategies argues for immunity and inflammation as a metanarrative of modern medicine.


Asunto(s)
Inmunidad Adaptativa/inmunología , Citocinas/fisiología , Inmunidad Innata/inmunología , Inflamación/inmunología , Interleucina-1/fisiología , Animales , Enfermedades Cardiovasculares/inmunología , Citocinas/genética , Citocinas/inmunología , Enfermedades Gastrointestinales/inmunología , Hematopoyesis/inmunología , Humanos , Interleucina-1/inmunología , Linfocitos/inmunología , Ratones , Ratones Noqueados , Familia de Multigenes , Neoplasias/inmunología , Enfermedades Neurodegenerativas/inmunología , Receptores de Citocinas/genética , Receptores de Citocinas/inmunología
8.
Nat Immunol ; 16(4): 354-65, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25729923

RESUMEN

Interleukin 37 (IL-37) and IL-1R8 (SIGIRR or TIR8) are anti-inflammatory orphan members of the IL-1 ligand family and IL-1 receptor family, respectively. Here we demonstrate formation and function of the endogenous ligand-receptor complex IL-37-IL-1R8-IL-18Rα. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Rα impaired the anti-inflammatory activity of IL-37. Whereas mice with transgenic expression of IL-37 (IL-37tg mice) with intact IL-1R8 were protected from endotoxemia, IL-1R8-deficient IL-37tg mice were not. Proteomic and transcriptomic investigations revealed that IL-37 used IL-1R8 to harness the anti-inflammatory properties of the signaling molecules Mer, PTEN, STAT3 and p62(dok) and to inhibit the kinases Fyn and TAK1 and the transcription factor NF-κB, as well as mitogen-activated protein kinases. Furthermore, IL-37-IL-1R8 exerted a pseudo-starvational effect on the metabolic checkpoint kinase mTOR. IL-37 thus bound to IL-18Rα and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program.


Asunto(s)
Subunidad alfa del Receptor de Interleucina-18/inmunología , Interleucina-1/inmunología , Leucocitos Mononucleares/inmunología , Receptores de Interleucina-1/inmunología , Transducción de Señal/inmunología , Animales , Línea Celular , Regulación de la Expresión Génica , Humanos , Inmunidad Innata , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Interleucina-1/genética , Subunidad alfa del Receptor de Interleucina-18/antagonistas & inhibidores , Subunidad alfa del Receptor de Interleucina-18/genética , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/patología , Lipopolisacáridos/farmacología , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/inmunología , Ratones , Ratones Transgénicos , FN-kappa B/genética , FN-kappa B/inmunología , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/inmunología , Unión Proteica , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/inmunología , Proteínas Proto-Oncogénicas c-fyn/genética , Proteínas Proto-Oncogénicas c-fyn/inmunología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/inmunología , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/inmunología , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/inmunología , Receptores de Interleucina-1/antagonistas & inhibidores , Receptores de Interleucina-1/deficiencia , Receptores de Interleucina-1/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/inmunología , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/inmunología , Tirosina Quinasa c-Mer
9.
Proc Natl Acad Sci U S A ; 120(45): e2306476120, 2023 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-37906644

RESUMEN

The IL-1 Family member IL-38 has been characterized primarily as an antiinflammatory cytokine in human and mouse models of systemic diseases. Here, we examined the role of IL-38 in the murine small intestine (SI). Immunostaining of SI revealed that IL-38 expression partially confines to intestinal stem cells. Cultures of intestinal organoids reveal IL-38 functions as a growth factor by increasing organoid size via inducing WNT3a. In contrast, organoids from IL-38-deficient mice develop more slowly. This reduction in size is likely due to the downregulation of intestinal stemness markers (i.e., Fzd5, Ephb2, and Olfm4) expression compared with wild-type organoids. The IL-38 binding to IL-1R6 and IL-1R9 is still a matter of debate. Therefore, to analyze the molecular mechanisms of IL-38 signaling, we also examined organoids from IL-1R9-deficient mice. Unexpectedly, these organoids, although significantly smaller than wild type, respond to IL-38, suggesting that IL-1R9 is not involved in IL-38 signaling in the stem cell crypt. Nevertheless, silencing of IL-1R6 disabled the organoid response to the growth property of IL-38, thus suggesting IL-1R6 as the main receptor used by IL-38 in the crypt compartment. In organoids from wild-type mice, IL-38 stimulation induced low concentrations of IL-1ß which contribute to organoid growth. However, high concentrations of IL-1ß have detrimental effects on the cultures that were prevented by treatment with recombinant IL-38. Overall, our data demonstrate an important regulatory function of IL-38 as a growth factor, and as an antiinflammatory molecule in the SI, maintaining homeostasis.


Asunto(s)
Mucosa Intestinal , Vía de Señalización Wnt , Animales , Ratones , Homeostasis , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Interleucinas/metabolismo , Mucosa Intestinal/metabolismo , Organoides/metabolismo , Células Madre/metabolismo
10.
Nat Immunol ; 14(5): 480-8, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23525089

RESUMEN

NOD2 receptor and the cytosolic protein kinase RIPK2 regulate NF-κB and MAP kinase signaling during bacterial infections, but the role of this immune axis during viral infections has not been addressed. We demonstrate that Nod2(-/-) and Ripk2(-/-) mice are hypersusceptible to infection with influenza A virus. Ripk2(-/-) cells exhibited defective autophagy of mitochondria (mitophagy), leading to enhanced mitochondrial production of superoxide and accumulation of damaged mitochondria, which resulted in greater activation of the NLRP3 inflammasome and production of IL-18. RIPK2 regulated mitophagy in a kinase-dependent manner by phosphorylating the mitophagy inducer ULK1. Accordingly, Ulk1(-/-) cells exhibited enhanced mitochondrial production of superoxide and activation of caspase-1. These results demonstrate a role for NOD2-RIPK2 signaling in protection against virally triggered immunopathology by negatively regulating activation of the NLRP3 inflammasome and production of IL-18 via ULK1-dependent mitophagy.


Asunto(s)
Alphainfluenzavirus/inmunología , Proteínas Portadoras/metabolismo , Inflamasomas/metabolismo , Mitocondrias/fisiología , Mitofagia , Infecciones por Orthomyxoviridae/inmunología , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor/metabolismo , Animales , Homólogo de la Proteína 1 Relacionada con la Autofagia , Caspasa 1/metabolismo , Células Cultivadas , Inmunidad Activa/genética , Interleucina-18/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Proteína Adaptadora de Señalización NOD2/genética , Proteína Adaptadora de Señalización NOD2/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor/genética , Transducción de Señal/genética , Superóxidos/metabolismo , Factores de Virulencia/genética
11.
Cell ; 140(6): 935-50, 2010 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-20303881

RESUMEN

Inflammation involving the innate and adaptive immune systems is a normal response to infection. However, when allowed to continue unchecked, inflammation may result in autoimmune or autoinflammatory disorders, neurodegenerative disease, or cancer. A variety of safe and effective anti-inflammatory agents are available, including aspirin and other nonsteroidal anti-inflammatories, with many more drugs under development. In particular, the new era of anti-inflammatory agents includes "biologicals" such as anticytokine therapies and small molecules that block the activity of kinases. Other anti-inflammatories currently in use or under development include statins, histone deacetylase inhibitors, PPAR agonists, and small RNAs. This Review discusses the current status of anti-inflammatory drug research and the development of new anti-inflammatory therapeutics.


Asunto(s)
Antiinflamatorios/uso terapéutico , Inflamación/tratamiento farmacológico , Animales , Antiinflamatorios/química , Antiinflamatorios/inmunología , Enfermedades Autoinmunes/tratamiento farmacológico , Diseño de Fármacos , Humanos , Inflamación/inmunología
12.
Proc Natl Acad Sci U S A ; 119(36): e2202577119, 2022 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-36037361

RESUMEN

Calcific aortic valve disease (CAVD) is common in people over the age of 65. Progressive valvular calcification is a characteristic of CAVD and due to chronic inflammation in aortic valve interstitial cells (AVICs) resulting in CAVD progression. IL-38 is a naturally occurring anti-inflammatory cytokine; here, we report lower levels of endogenous IL-38 in AVICs isolated from patients' CAVD valves compared to AVICs from non-CAVD valves. Recombinant IL-38 suppressed spontaneous inflammatory activity and calcium deposition in cultured AVICs. In mice, knockdown of IL-38 enhanced the production of inflammatory mediators in murine AVICs exposed to the proinflammatory stimulant matrilin-2. We also observed that in cultured AVICs matrilin-2 stimulation activated the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome with procaspase-1 cleavage into active caspase-1. The addition of IL-38 to matrilin-2-treated AVICs suppressed caspase-1 activation and reduced the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, runt-related transcription factor 2, and alkaline phosphatase. Aged IL-38-deficient mice fed a high-fat diet exhibited aortic valve lesions compared to aged wild-type mice fed the same diet. The interleukin-1 receptor 9 (IL-1R9) is the putative receptor mediating the anti-inflammatory properties of IL-38; we observed that IL-1R9-deficient mice exhibited spontaneous aortic valve thickening and greater calcium deposition in AVICs compared to wild-type mice. These data demonstrate that IL-38 suppresses spontaneous and stimulated osteogenic activity in aortic valve via inhibition of the NLRP3 inflammasome and caspase-1. The findings of this study suggest that IL-38 has therapeutic potential for prevention of CAVD progression.


Asunto(s)
Estenosis de la Válvula Aórtica , Calcinosis , Interleucinas , Animales , Antiinflamatorios/farmacología , Válvula Aórtica/metabolismo , Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/tratamiento farmacológico , Estenosis de la Válvula Aórtica/genética , Estenosis de la Válvula Aórtica/metabolismo , Calcinosis/tratamiento farmacológico , Calcio/metabolismo , Caspasas/metabolismo , Células Cultivadas , Humanos , Inflamasomas/metabolismo , Interleucina-1 , Interleucinas/genética , Interleucinas/metabolismo , Interleucinas/farmacología , Proteínas Matrilinas/farmacología , Ratones , Ratones Endogámicos NOD , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Osteogénesis , Receptores de Interleucina-9/genética , Proteínas Recombinantes/farmacología
13.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33649199

RESUMEN

Interleukin-1ß (IL-1ß)-mediated inflammation suppresses antitumor immunity, leading to the generation of a tumor-permissive environment, tumor growth, and progression. Here, we demonstrate that nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in melanoma is linked to IL-1ß production, inflammation, and immunosuppression. Analysis of cancer genome datasets (TCGA and GTEx) revealed greater NLRP3 and IL-1ß expression in cutaneous melanoma samples (n = 469) compared to normal skin (n = 324), with a highly significant correlation between NLRP3 and IL-1ß (P < 0.0001). We show the formation of the NLRP3 inflammasome in biopsies of metastatic melanoma using fluorescent resonance energy transfer analysis for NLRP3 and apoptosis-associated speck-like protein containing a CARD. In vivo, tumor-associated NLRP3/IL-1 signaling induced expansion of myeloid-derived suppressor cells (MDSCs), leading to reduced natural killer and CD8+ T cell activity concomitant with an increased presence of regulatory T (Treg) cells in the primary tumors. Either genetic or pharmacological inhibition of tumor-derived NLRP3 by dapansutrile (OLT1177) was sufficient to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth. Additionally, we observed that the combination of NLRP3 inhibition and anti-PD-1 treatment significantly increased the antitumor efficacy of the monotherapy by limiting MDSC-mediated T cell suppression and tumor progression. These data show that NLRP3 activation in melanoma cells is a protumor mechanism, which induces MDSCs expansion and immune evasion. We conclude that inhibition of NLRP3 can augment the efficacy of anti-PD-1 therapy.


Asunto(s)
Melanoma Experimental/inmunología , Células Supresoras de Origen Mieloide/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Proteínas de Neoplasias/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Humanos , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Melanoma Experimental/genética , Melanoma Experimental/patología , Ratones , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteínas de Neoplasias/genética , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T Reguladores/inmunología
14.
J Neuroinflammation ; 20(1): 147, 2023 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-37349821

RESUMEN

BACKGROUND: Parkinson's disease (PD) is characterized by a progressive degeneration of dopaminergic neurons, which leads to irreversible loss of peripheral motor functions. Death of dopaminergic neurons induces an inflammatory response in microglial cells, which further exacerbates neuronal loss. Reducing inflammation is expected to ameliorate neuronal loss and arrest motor dysfunctions. Because of the contribution of the NLRP3 inflammasome to the inflammatory response in PD, we targeted NLRP3 using the specific inhibitor OLT1177®. METHODS: We evaluated the effectiveness of OLT1177® in reducing the inflammatory response in an MPTP neurotoxic model of PD. Using a combination of in vitro and in vivo studies, we analyzed the effects of NLRP3 inhibition on pro-inflammatory markers in the brain, α-synuclein aggregation, and dopaminergic neuron survival. We also determined the effects of OLT1177® on locomotor deficits associated with MPTP and brain penetrance. RESULTS: Treatment with OLT1177® prevented the loss of motor function, reduced the levels of α-synuclein, modulated pro-inflammatory markers in the nigrostriatal areas of the brain, and protected dopaminergic neurons from degeneration in the MPTP model of PD. We also demonstrated that OLT1177® crosses the blood-brain barrier and reaches therapeutic concentrations in the brain. CONCLUSIONS: These data suggest that targeting the NLRP3 inflammasome by OLT1177® may be a safe and novel therapeutic approach to arrest neuroinflammation and protect against neurological deficits of Parkinson's disease in humans.


Asunto(s)
Enfermedad de Parkinson , Humanos , Animales , Ratones , Enfermedad de Parkinson/tratamiento farmacológico , alfa-Sinucleína/farmacología , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Neuronas Dopaminérgicas , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad
15.
Blood ; 138(17): 1554-1569, 2021 10 28.
Artículo en Inglés | MEDLINE | ID: mdl-34077954

RESUMEN

Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.


Asunto(s)
Enfermedad de Erdheim-Chester/genética , Inflamación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Células Cultivadas , Epigénesis Genética , Enfermedad de Erdheim-Chester/inmunología , Enfermedad de Erdheim-Chester/patología , Humanos , Inmunidad , Inflamación/inmunología , Inflamación/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Oncogenes , Mutación Puntual , Proteínas Proto-Oncogénicas B-raf/inmunología
16.
Proc Natl Acad Sci U S A ; 117(50): 32145-32154, 2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33257576

RESUMEN

Numerous studies demonstrate that neuroinflammation is a key player in the progression of Alzheimer's disease (AD). Interleukin (IL)-1ß is a main inducer of inflammation and therefore a prime target for therapeutic options. The inactive IL-1ß precursor requires processing by the the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome into a mature and active form. Studies have shown that IL-1ß is up-regulated in brains of patients with AD, and that genetic inactivation of the NLRP3 inflammasome improves behavioral tests and synaptic plasticity phenotypes in a murine model of the disease. In the present study, we analyzed the effect of pharmacological inhibition of the NLRP3 inflammasome using dapansutrile (OLT1177), an oral NLRP3-specific inhibitor that is safe in humans. Six-month-old WT and APP/PS1 mice were fed with standard mouse chow or OLT1177-enriched chow for 3 mo. The Morris water maze test revealed an impaired learning and memory ability of 9-mo-old APP/PS1 mice (P = 0.001), which was completely rescued by OLT1177 fed to mice (P = 0.008 to untreated APP/PS1). Furthermore, our findings revealed that 3 mo of OLT1177 diet can rescue synaptic plasticity in this mouse model of AD (P = 0.007 to untreated APP/PS1). In addition, microglia were less activated (P = 0.07) and the number of plaques was reduced in the cortex (P = 0.03) following NLRP3 inhibition with OLT1177 administration. We also observed an OLT1177 dose-dependent normalization of plasma metabolic markers of AD to those of WT mice. This study suggests the therapeutic potential of treating neuroinflammation with an oral inhibitor of the NLRP3 inflammasome.


Asunto(s)
Enfermedad de Alzheimer/complicaciones , Disfunción Cognitiva/tratamiento farmacológico , Inflamasomas/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Nitrilos/farmacología , Administración Oral , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/inmunología , Precursor de Proteína beta-Amiloide/genética , Animales , Técnicas de Observación Conductual , Conducta Animal/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/inmunología , Corteza Cerebral/patología , Disfunción Cognitiva/inmunología , Disfunción Cognitiva/patología , Modelos Animales de Enfermedad , Humanos , Inflamasomas/inmunología , Masculino , Ratones , Ratones Transgénicos , Microglía/efectos de los fármacos , Microglía/inmunología , Microglía/patología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/inmunología , Nitrilos/uso terapéutico , Presenilina-1/genética , Memoria Espacial/efectos de los fármacos
17.
Proc Natl Acad Sci U S A ; 117(32): 18951-18953, 2020 08 11.
Artículo en Inglés | MEDLINE | ID: mdl-32699149

RESUMEN

Around the tenth day after diagnosis, ∼20% of patients with coronavirus disease 2019 (COVID-19)-associated pneumonia evolve toward severe oxygen dependence (stage 2b) and acute respiratory distress syndrome (stage 3) associated with systemic inflammation often termed a "cytokine storm." Because interleukin-1 (IL-1) blocks the production of IL-6 and other proinflammatory cytokines, we treated COVID-19 patients early in the disease with the IL-1 receptor antagonist, anakinra. We retrospectively compared 22 patients from three different centers in France with stages 2b and 3 COVID-19-associated pneumonia presenting with acute severe respiratory failure and systemic inflammation who received either standard-of-care treatment alone (10 patients) or combined with intravenous anakinra (12 patients). Treatment started at 300 mg⋅d-1 for 5 d, then tapered with lower dosing over 3 d. Both populations were comparable for age, comorbidities, clinical stage, and elevated biomarkers of systemic inflammation. All of the patients treated with anakinra improved clinically (P < 0.01), with no deaths, significant decreases in oxygen requirements (P < 0.05), and more days without invasive mechanical ventilation (P < 0.06), compared with the control group. The effect of anakinra was rapid, as judged by significant decrease of fever and C-reactive protein at day 3. A mean total dose of 1,950 mg was infused with no adverse side effects or bacterial infection. We conclude that early blockade of the IL-1 receptor is therapeutic in acute hyperinflammatory respiratory failure in COVID-19 patients.


Asunto(s)
Antiinflamatorios/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Insuficiencia Respiratoria/tratamiento farmacológico , Anciano , Antiinflamatorios/administración & dosificación , COVID-19 , Estudios de Casos y Controles , Infecciones por Coronavirus/complicaciones , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Inyecciones Intravenosas , Proteína Antagonista del Receptor de Interleucina 1/administración & dosificación , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/etiología , Insuficiencia Respiratoria/etiología
18.
Int J Mol Sci ; 24(3)2023 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-36768634

RESUMEN

Trained immunity is the process of long-term functional reprogramming (a de facto innate immune memory) of innate immune cells such as monocytes and macrophages after an exposure to pathogens, vaccines, or their ligands. The induction of trained immunity is mediated through epigenetic and metabolic mechanisms. Apart from exogenous stimuli, trained immunity can be induced by endogenous compounds such as oxidized LDL, urate, fumarate, but also cytokines including IL-1α and IL-1ß. Here, we show that also recombinant IL-36γ, a pro-inflammatory cytokine of the IL-1-family, is able to induce trained immunity in primary human monocytes, demonstrated by higher cytokine responses and an increase in cellular metabolic pathways both regulated by epigenetic histone modifications. These effects could be inhibited by the IL-36 receptor antagonist as well as by IL-38, an anti-inflammatory cytokine of the IL-1 family which shares its main receptor with IL-36 (IL-1R6). Further, we demonstrated that trained immunity induced by IL-36γ is mediated by NF-κB and mTOR signaling. The inhibitory effect of IL-38 on IL-36γ-induced trained immunity was confirmed in experiments using bone marrow of IL-38KO and WT mice. These results indicate that exposure to IL-36γ results in long-term pro-inflammatory changes in monocytes which can be inhibited by IL-38. Recombinant IL-38 could therefore potentially be used as a therapeutic intervention for diseases characterized by exacerbated trained immunity.


Asunto(s)
Inmunidad Innata , Inmunidad Entrenada , Humanos , Animales , Ratones , Interleucinas/farmacología , Interleucinas/metabolismo , Macrófagos/metabolismo , Citocinas/metabolismo
19.
J Biol Chem ; 296: 100630, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33823154

RESUMEN

Unchecked inflammation can result in severe diseases with high mortality, such as macrophage activation syndrome (MAS). MAS and associated cytokine storms have been observed in COVID-19 patients exhibiting systemic hyperinflammation. Interleukin-18 (IL-18), a proinflammatory cytokine belonging to the IL-1 family, is elevated in both MAS and COVID-19 patients, and its level is known to correlate with the severity of COVID-19 symptoms. IL-18 binds its specific receptor IL-1 receptor 5 (IL-1R5, also known as IL-18 receptor alpha chain), leading to the recruitment of the coreceptor, IL-1 receptor 7 (IL-1R7, also known as IL-18 receptor beta chain). This heterotrimeric complex then initiates downstream signaling, resulting in systemic and local inflammation. Here, we developed a novel humanized monoclonal anti-IL-1R7 antibody to specifically block the activity of IL-18 and its inflammatory signaling. We characterized the function of this antibody in human cell lines, in freshly obtained peripheral blood mononuclear cells (PBMCs) and in human whole blood cultures. We found that the anti-IL-1R7 antibody significantly suppressed IL-18-mediated NFκB activation, reduced IL-18-stimulated IFNγ and IL-6 production in human cell lines, and reduced IL-18-induced IFNγ, IL-6, and TNFα production in PBMCs. Moreover, the anti-IL-1R7 antibody significantly inhibited LPS- and Candida albicans-induced IFNγ production in PBMCs, as well as LPS-induced IFNγ production in whole blood cultures. Our data suggest that blocking IL-1R7 could represent a potential therapeutic strategy to specifically modulate IL-18 signaling and may warrant further investigation into its clinical potential for treating IL-18-mediated diseases, including MAS and COVID-19.


Asunto(s)
Antiinflamatorios/farmacología , Anticuerpos Monoclonales/farmacología , Anticuerpos Neutralizantes/farmacología , Factores Inmunológicos/farmacología , Interleucina-18/genética , Receptores de Interleucina-18/genética , Antiinflamatorios/metabolismo , Anticuerpos Monoclonales/biosíntesis , Anticuerpos Neutralizantes/biosíntesis , Candida albicans/crecimiento & desarrollo , Candida albicans/patogenicidad , Regulación de la Expresión Génica , Células HEK293 , Humanos , Factores Inmunológicos/biosíntesis , Inflamación , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-18/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/microbiología , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Síndrome de Activación Macrofágica/tratamiento farmacológico , FN-kappa B/genética , FN-kappa B/inmunología , Cultivo Primario de Células , Receptores de Interleucina-18/antagonistas & inhibidores , Receptores de Interleucina-18/inmunología , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Tratamiento Farmacológico de COVID-19
20.
Eur J Immunol ; 51(3): 662-671, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33125159

RESUMEN

The IL-1 family member IL-38 (IL1F10) suppresses inflammatory and autoimmune conditions. Here, we report that plasma concentrations of IL-38 in 288 healthy Europeans correlate positively with circulating memory B cells and plasmablasts. IL-38 correlated negatively with age (p = 0.02) and was stable in 48 subjects for 1 year. In comparison with primary keratinocytes, IL1F10 expression in CD19+ B cells from PBMC was lower, whereas cell-associated IL-38 expression was comparable. In vitro, IL-38 is released from CD19+ B cells after stimulation with rituximab. Intravenous LPS in humans failed to induce circulating IL-38, compared to 100-fold induction of IL-6 and IL-1 receptor antagonist. In a cohort of 296 subjects with body mass index > 27 at high risk for cardiovascular disease, IL-38 plasma concentrations were significantly lower than in healthy subjects (p < 0.0001), and lowest in those with metabolic syndrome (p < 0.05). IL-38 also correlated inversely with high sensitivity C-reactive protein (p < 0.01), IL-6, IL-1Ra, and leptin (p < 0.05). We conclude that a relative deficiency of the B cell product IL-38 is associated with increased systemic inflammation in aging, cardiovascular and metabolic disease, and is consistent with IL-38 as an anti-inflammatory cytokine.


Asunto(s)
Linfocitos B/inmunología , Enfermedades Cardiovasculares/inmunología , Citocinas/inmunología , Interleucinas/inmunología , Sobrepeso/inmunología , Adulto , Antígenos CD19/inmunología , Estudios de Cohortes , Femenino , Humanos , Interleucina-1/inmunología , Interleucina-6/inmunología , Masculino , Receptores de Interleucina-1/inmunología , Riesgo , Adulto Joven
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