Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
1.
mBio ; 15(3): e0008324, 2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38376210

RESUMEN

Mice that lack the genes for IL-27, or the IL-27 receptor, and infected with Toxoplasma gondii develop T cell-mediated pathology. Here, studies were performed to determine the impact of endogenous IL-27 on the immune response to T. gondii in wild-type (WT) mice. Analysis of infected mice revealed the early production of IL-27p28 by a subset of Ly6Chi, inflammatory monocytes, and sustained IL-27p28 production at sites of acute and chronic infection. Administration of anti-IL-27p28 prior to infection resulted in an early (day 5) increase in levels of macrophage and granulocyte activation, as well as enhanced effector T cell responses, as measured by both cellularity, cytokine production, and transcriptional profiling. This enhanced acute response led to immune pathology, while blockade during the chronic phase of infection resulted in enhanced T cell responses but no systemic pathology. In the absence of IL-27, the enhanced monocyte responses observed at day 10 were a secondary consequence of activated CD4+ T cells. Thus, in WT mice, IL-27 has distinct suppressive effects that impact innate and adaptive immunity during different phases of this infection. IMPORTANCE: The molecule IL-27 is critical in limiting the immune response to the parasite Toxoplasma gondii. In the absence of IL-27, a lethal, overactive immune response develops during infection. However, when exactly in the course of infection this molecule is needed was unclear. By selectively inhibiting IL-27 during this parasitic infection, we discovered that IL-27 was only needed during, but not prior to, infection. Additionally, IL-27 is only needed in the active areas in which the parasite is replicating. Finally, our work found that a previously unstudied cell type, monocytes, was regulated by IL-27, which contributes further to our understanding of the regulatory networks established by this molecule.


Asunto(s)
Interleucina-27 , Toxoplasma , Toxoplasmosis , Animales , Ratones , Interleucina-27/metabolismo , Ratones Endogámicos C57BL , Monocitos , Linfocitos T , Toxoplasmosis/parasitología
2.
Cell Rep ; 42(3): 112147, 2023 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-36827187

RESUMEN

Interleukin-18 (IL-18) promotes natural killer (NK) and T cell production of interferon (IFN)-γ, a key factor in resistance to Toxoplasma gondii, but previous work has shown a limited role for endogenous IL-18 in control of this parasite. Although infection with T. gondii results in release of IL-18, the production of IFN-γ induces high levels of the IL-18 binding protein (IL-18BP). Antagonism of IL-18BP with a "decoy-to-the-decoy" (D2D) IL-18 construct that does not signal but rather binds IL-18BP results in enhanced innate lymphoid cell (ILC) and T cell responses and improved parasite control. In addition, the use of IL-18 resistant to IL-18BP ("decoy-resistant" IL-18 [DR-18]) is more effective than exogenous IL-18 at promoting innate resistance to infection. DR-18 enhances CD4+ T cell production of IFN-γ but results in CD4+ T cell-mediated pathology. Thus, endogenous IL-18BP restrains aberrant immune pathology, and this study highlights strategies that can be used to tune this regulatory pathway for optimal anti-pathogen responses.


Asunto(s)
Toxoplasma , Toxoplasmosis Animal , Humanos , Animales , Interleucina-18/metabolismo , Células Asesinas Naturales , Interleucina-12/metabolismo , Inmunidad Innata
3.
Nat Commun ; 13(1): 4018, 2022 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-35821371

RESUMEN

The kidney has tremendous capacity to repair after acute injury, however, pathways guiding adaptive and fibrotic repair are poorly understood. We developed a model of adaptive and fibrotic kidney regeneration by titrating ischemic injury dose. We performed detailed biochemical and histological analysis and profiled transcriptomic changes at bulk and single-cell level (> 110,000 cells) over time. Our analysis highlights kidney proximal tubule cells as key susceptible cells to injury. Adaptive proximal tubule repair correlated with fatty acid oxidation and oxidative phosphorylation. We identify a specific maladaptive/profibrotic proximal tubule cluster after long ischemia, which expresses proinflammatory and profibrotic cytokines and myeloid cell chemotactic factors. Druggability analysis highlights pyroptosis/ferroptosis as vulnerable pathways in these profibrotic cells. Pharmacological targeting of pyroptosis/ferroptosis in vivo pushed cells towards adaptive repair and ameliorates fibrosis. In summary, our single-cell analysis defines key differences in adaptive and fibrotic repair and identifies druggable pathways for pharmacological intervention to prevent kidney fibrosis.


Asunto(s)
Lesión Renal Aguda , Riñón , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/genética , Lesión Renal Aguda/metabolismo , Fibrosis , Humanos , Riñón/metabolismo , Regeneración , Análisis de la Célula Individual
4.
Nat Immunol ; 23(6): 947-959, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35552540

RESUMEN

Inflammation is an important component of fibrosis but immune processes that orchestrate kidney fibrosis are not well understood. Here we apply single-cell sequencing to a mouse model of kidney fibrosis. We identify a subset of kidney tubule cells with a profibrotic-inflammatory phenotype characterized by the expression of cytokines and chemokines associated with immune cell recruitment. Receptor-ligand interaction analysis and experimental validation indicate that CXCL1 secreted by profibrotic tubules recruits CXCR2+ basophils. In mice, these basophils are an important source of interleukin-6 and recruitment of the TH17 subset of helper T cells. Genetic deletion or antibody-based depletion of basophils results in reduced renal fibrosis. Human kidney single-cell, bulk gene expression and immunostaining validate a function for basophils in patients with kidney fibrosis. Collectively, these studies identify basophils as contributors to the development of renal fibrosis and suggest that targeting these cells might be a useful clinical strategy to manage chronic kidney disease.


Asunto(s)
Basófilos , Insuficiencia Renal Crónica , Animales , Fibrosis , Humanos , Riñón/metabolismo , Túbulos Renales , Ratones , Insuficiencia Renal Crónica/metabolismo , Análisis de la Célula Individual
5.
Cell Rep ; 36(8): 109591, 2021 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-34433030

RESUMEN

The relationship between B cells and CD4 T cells has been carefully studied, revealing a collaborative effort in which B cells promote the activation, differentiation, and expansion of CD4 T cells while the so-called "helper" cells provide signals to B cells, influencing their class switching and fate. Interactions between B cells and CD8 T cells are not as well studied, although CD8 T cells exhibit an accelerated contraction after certain infections in B-cell-deficient mice. Here, we find that B cells significantly enhance primary CD8 T cell responses after vaccination. Moreover, memory CD8 numbers and function are impaired in B-cell-deficient animals, leading to increased susceptibility to bacterial challenge. We also show that interleukin-27 production by B cells contributes to their impact on primary, but not memory, CD8 responses. Better understanding of the interactions between CD8 T cells and B cells may aid in the design of more effective future vaccine strategies.


Asunto(s)
Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica , Interleucina-27/inmunología , Interleucina-27/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Vacunas de Subunidad/inmunología , Animales , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , COVID-19/inmunología , Humanos , Recuento de Linfocitos , Ratones , Ratones Endogámicos C57BL , Receptores Virales/inmunología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunación
6.
Immunohorizons ; 5(6): 384-394, 2021 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-34088852

RESUMEN

Resistance to the parasite Toxoplasma gondii is mediated by NK and T cell production of IFN-γ, but the failure to contract this response can lead to severe T cell-dependent immunopathology. Although the cytokines IL-10 and IL-27 prevent immune hyperactivity during toxoplasmosis, inhibitory receptors, expressed by NK and T cells, are also implicated in this process. The inhibitory receptor TIGIT is expressed on NK and T cells and competes with the costimulatory receptor CD226 for binding of the ligand CD155. During toxoplasmosis, the activation of NK and T cells is associated with increased expression of CD226 and TIGIT, whereas DCs express increased levels of CD155. To determine if the loss of TIGIT impacts NK and T cell activities, wild-type and TIGIT knockout mice were infected with T. gondii During the acute stage of infection, wild-type and TIGIT knockout mice had comparable parasite burdens and similar NK and T cell responses. Likewise, during the chronic phase of this infection, the loss of TIGIT did not affect the magnitude or phenotype of the T cell response nor the ability to control pathogen load. These data suggest that during toxoplasmosis, despite upregulation of relevant ligands, TIGIT signaling does not limit NK and T cell activities. Thus, TIGIT-independent mechanisms dominate the restraint of the immune response during toxoplasmosis.


Asunto(s)
Células Asesinas Naturales/inmunología , Receptores Inmunológicos/metabolismo , Linfocitos T/inmunología , Toxoplasmosis/inmunología , Animales , Antígenos de Diferenciación de Linfocitos T/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Células Asesinas Naturales/metabolismo , Masculino , Ratones , Ratones Noqueados , Carga de Parásitos , Receptores Inmunológicos/genética , Receptores Virales/metabolismo , Linfocitos T/metabolismo , Toxoplasma/inmunología , Toxoplasma/aislamiento & purificación , Toxoplasmosis/sangre , Toxoplasmosis/parasitología
7.
Biol Open ; 9(12)2020 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-33234703

RESUMEN

Infection with human immunodeficiency virus 1 (HIV-1) remains incurable because long-lived, latently-infected cells persist during prolonged antiretroviral therapy. Attempts to pharmacologically reactivate and purge the latent reservoir with latency reactivating agents (LRAs) such as protein kinase C (PKC) agonists (e.g. ingenol A) or histone deacetylase (HDAC) inhibitors (e.g. SAHA) have shown promising but incomplete efficacy. Using the J-Lat T cell model of HIV latency, we found that the plant-derived compound harmine enhanced the efficacy of existing PKC agonist LRAs in reactivating latently-infected cells. Treatment with harmine increased not only the number of reactivated cells but also increased HIV transcription and protein expression on a per-cell basis. Importantly, we observed a synergistic effect when harmine was used in combination with ingenol A and the HDAC inhibitor SAHA. An investigation into the mechanism revealed that harmine, when used with LRAs, increased the activity of NFκB, MAPK p38, and ERK1/2. Harmine treatment also resulted in reduced expression of HEXIM1, a negative regulator of transcriptional elongation. Thus, harmine enhanced the effects of LRAs by increasing the availability of transcription factors needed for HIV reactivation and promoting transcriptional elongation. Combination therapies with harmine and LRAs could benefit patients by achieving deeper reactivation of the latent pool of HIV provirus.


Asunto(s)
Diterpenos/farmacología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/fisiología , Harmina/farmacología , Nylons/farmacología , Pirroles/farmacología , Latencia del Virus/efectos de los fármacos , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , Humanos , Activación de Linfocitos/efectos de los fármacos , Proteína Quinasa C/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Activación Viral/efectos de los fármacos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA