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1.
Kidney Int ; 104(2): 279-292, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37098380

RESUMO

Urinary tract infections are common. Here, we delineate a role of extracellular DNA trap (ET) formation in kidney antibacterial defense and determine mechanisms of their formation in the hyperosmotic environment of the kidney medulla. ET of granulocytic and monocytic origin were present in the kidneys of patients with pyelonephritis along with systemically elevated citrullinated histone levels. Inhibition of the transcription coregulatory, peptidylarginine deaminase 4 (PAD4), required for ET formation, prevented kidney ET formation and promoted pyelonephritis in mice. ETs predominantly accumulated in the kidney medulla. The role of medullary sodium chloride and urea concentrations in ET formation was then investigated. Medullary-range sodium chloride, but not urea, dose-, time- and PAD4-dependently induced ET formation even in the absence of other stimuli. Moderately elevated sodium chloride promoted myeloid cell apoptosis. Sodium gluconate also promoted cell death, proposing a role for sodium ions in this process. Sodium chloride induced myeloid cell calcium influx. Calcium ion-free media or -chelation reduced sodium chloride-induced apoptosis and ET formation while bacterial lipopolysaccharide amplified it. Autologous serum improved bacterial killing in the presence of sodium chloride-induced ET. Depletion of the kidney sodium chloride gradient by loop diuretic therapy diminished kidney medullary ET formation and increased pyelonephritis severity. Thus, our data demonstrate that ETs may protect the kidney against ascending uropathogenic E. coli and delineate kidney medullary range sodium chloride concentrations as novel inducers of programmed myeloid cell death.


Assuntos
Armadilhas Extracelulares , Pielonefrite , Camundongos , Animais , Cloreto de Sódio/farmacologia , Neutrófilos , Monócitos , Cálcio , Escherichia coli , Rim , Pielonefrite/tratamento farmacológico , DNA , Ureia
2.
Eur J Immunol ; 52(8): 1258-1272, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35527392

RESUMO

Renal immune cells serve as sentinels against ascending bacteria but also promote detrimental inflammation. The kidney medulla is characterized by extreme electrolyte concentrations. We here address how its main osmolytes, NaCl and urea, regulate tubular cell cytokine expression and monocyte chemotaxis. In the healthy human kidney, more monocytes were detected in medulla than cortex. The monocyte gradient was attenuated in patients with medullary NaCl depletion by loop diuretic therapy and in the nephrotic syndrome. Renal tubular epithelial cell gene expression responded similarly to NaCl and tonicity control mannitol, but not urea. NaCl significantly upregulated chemotactic cytokines, most markedly CCL26, CCL2, and CSF1. This induction was inhibited by the ROS scavenger n-acetylcysteine. In contrast, urea, the main medullary osmolyte in catabolism, dampened tubular epithelial CCL26 and CSF1 expression. Renal medullary chemokine and monocyte marker expression decreased in catabolic mice. NaCl-, but not urea-stimulated tubular epithelium or CCL2 and CCL26, promoted human classical monocyte migration. CCL26 improved bactericidal function. In the human kidney medulla, monocyte densities correlated with tubular CCL26 protein abundance. In summary, medullary-range NaCl, but not urea, promotes tubular cytokine expression and monocyte recruitment. This may contribute to the pyelonephritis vulnerability in catabolism but can possibly be harnessed against pathologic inflammation.


Assuntos
Medula Renal , Cloreto de Sódio , Animais , Citocinas/metabolismo , Células Epiteliais/metabolismo , Humanos , Inflamação/metabolismo , Medula Renal/metabolismo , Camundongos , Monócitos/metabolismo , Cloreto de Sódio/metabolismo , Cloreto de Sódio/farmacologia , Ureia/metabolismo , Ureia/farmacologia
3.
Cardiovasc Res ; 117(6): 1510-1522, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-32717023

RESUMO

AIMS: Monocytes are central for atherosclerotic vascular inflammation. The human non-classical, patrolling subtype, which expresses high levels of CD16 and fractalkine receptor CX3CR1, strongly associates with cardiovascular events. This is most marked in renal failure, a condition with excess atherosclerosis morbidity. The underlying mechanism is not understood. This study investigated how human CD16+ monocytes modulate endothelial cell function. METHODS AND RESULTS: In patients with kidney failure, CD16+ monocyte counts were elevated and dynamically decreased within a year after transplantation, chiefly due to a drop in CD14+CD16+ cells. The CX3CR1 ligand CX3CL1 was similarly elevated in the circulation of humans and mice with renal impairment. CX3CL1 up-regulation was also observed close to macrophage rich human coronary artery plaques. To investigate a mechanistic basis of this association, CD16+CX3CR1HIGH monocytes were co-incubated with primary human endothelium in vitro. Compared to classical CD14+ monocytes or transwell cocultures, CD16+ monocytes enhanced endothelial STAT1 and NF-κB p65 phosphorylation, up-regulated expression of CX3CL1 and interleukin-1ß, numerous CCL and CXCL chemokines and molecules promoting leucocyte patrolling and adhesion such as ICAM1 and VCAM1. Genes required for vasodilatation including endothelial nitric oxide synthase decreased while endothelial collagen production increased. Uraemic patients' monocytes enhanced endothelial CX3CL1 even more markedly. Their receptor CX3CR1 was required for enhanced aortic endothelial stiffness in murine atherosclerosis with renal impairment. CX3CR1 dose-dependently modulated monocyte-contact-dependent gene expression in human endothelium. CONCLUSION: By demonstrating endothelial proatherosclerotic gene regulation in direct contact with CD16+ monocytes, in part via cellular CX3CR1-CX3CL1 interaction, our data delineate a mechanism how this celltype can increase cardiovascular risk.


Assuntos
Aterosclerose/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , Quimiocina CX3CL1/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Monócitos/metabolismo , Placa Aterosclerótica , Receptores de IgG/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Receptor 1 de Quimiocina CX3C/genética , Comunicação Celular , Células Cultivadas , Quimiocina CX3CL1/genética , Técnicas de Cocultura , Modelos Animais de Doenças , Proteínas Ligadas por GPI/metabolismo , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Nefropatias/imunologia , Nefropatias/metabolismo , Nefropatias/terapia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Fenótipo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transdução de Sinais , Uremia/imunologia , Uremia/metabolismo
4.
Eur J Immunol ; 51(2): 354-367, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32926407

RESUMO

Peritoneal dialysis (PD) employs hypertonic glucose to remove excess water and uremic waste. Peritoneal membrane failure limits its long-term use. T-cell cytokines promote this decline. T-cell differentiation is critically determined by the microenvironment. We here study how PD-range hypertonic glucose regulates T-cell polarization and IL-17 production. In the human peritoneal cavity, CD3+ cell numbers increased in PD. Single cell RNA sequencing detected expression of T helper (Th) 17 signature genes RORC and IL23R. In vitro, PD-range glucose stimulated spontaneous and amplified cytokine-induced Th17 polarization. Osmotic controls l-glucose and d-mannose demonstrate that induction of IL-17A is a substance-independent, tonicity dose-dependent process. PD-range glucose upregulated glycolysis and increased the proportion of dysfunctional mitochondria. Blockade of reactive-oxygen species (ROS) prevented IL-17A induction in response to PD-range glucose. Peritoneal mesothelium cultured with IL-17A or IL17F produced pro-inflammatory cytokines IL-6, CCL2, and CX3CL1. In PD patients, peritoneal IL-17A positively correlated with CX3CL1 concentrations. PD-range glucose-stimulated, but neither identically treated Il17a-/- Il17f-/- nor T cells cultured with the ROS scavenger N-acetylcysteine enhanced mesothelial CX3CL1 expression. Our data delineate PD-range hypertonic glucose as a novel inducer of Th17 polarization in a mitochondrial-ROS-dependent manner. Modulation of tonicity-mediated effects of PD solutions may improve membrane survival.


Assuntos
Epitélio/imunologia , Glucose/imunologia , Inflamação/imunologia , Interleucina-17/imunologia , Peritônio/imunologia , Células Th17/imunologia , Animais , Células Cultivadas , Quimiocina CCL2/imunologia , Quimiocina CXCL1/imunologia , Feminino , Humanos , Interleucina-6/imunologia , Masculino , Manose/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mitocôndrias/imunologia , Diálise Peritoneal/métodos , Espécies Reativas de Oxigênio/imunologia , Regulação para Cima/imunologia
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