Inhibition of Urea Transporter (UT)-B Modulates LPS-Induced Inflammatory Responses in BV2 Microglia and N2a Neuroblastoma Cells

Jones, Aimée C.; Pinki, Farhana; Stewart, Gavin; Costello, Derek A.

doi:10.1007/s11064-021-03283-4

Cited by 8 publications

(8 citation statements)

References 39 publications

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“…Murine BV2 microglia and N2a neuroblastoma cells were grown in Dulbecco’s modified Eagle’s medium (DMEM/F12; Lonza or Sigma-Aldrich, UK) containing heat-inactivated foetal bovine serum (FBS; 10%) and penicillin–streptomycin (100 U/ml; Gibco, UK), and maintained as previously described [ 17 , 22 ]. In brief, cells were plated in 24-well culture plates at a density of 1.5 × 10 5 cells/well and incubated overnight in a humidified environment at 37 °C/5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…Supernatant concentration of TNF-α and interleukin (IL)-6 was determined by enzyme-linked immunosorbent assay (ELISA), according to the manufacturer’s guidelines (Biolegend, UK). Concentration of nitrite was measured in cell supernatants using the Griess assay (Sigma-Aldrich, UK) as previously described [ 17 , 22 ].…”

Section: Methodsmentioning

confidence: 99%

“…The impact of inflammatory insults on neuronal and cognitive dysfunction has been widely reported, and we among others have illustrated the key role of microglial Toll-like receptors (TLRs) in mediating these effects [12][13][14][15][16][17]. In recent years, TLR2 has been implicated as a critical regulator of inflammation in the brain [18,19].…”

Section: Introductionmentioning

confidence: 99%

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Palmitic Acid and Oleic Acid Differently Modulate TLR2-Mediated Inflammatory Responses in Microglia and Macrophages

et al. 2022

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The relationship between systemic immunity and neuroinflammation is widely recognised. Infiltration of peripheral immune cells to the CNS during certain chronic inflammatory states contributes significantly to neuropathology. Obesity and its co-morbidities are primary risk factors for neuroinflammatory and neurodegenerative conditions, including Alzheimer’s disease (AD). Dietary fats are among the most proinflammatory components of the obesogenic diet and play a prominent role in the low-grade systemic inflammation associated with the obese state. Saturated fatty acid (SFA) is largely implicated in the negative consequences of obesity, while the health benefits of monounsaturated fatty acid (MUFA) are widely acknowledged. The current study sought to explore whether SFA and MUFA differently modulate inflammatory responses in the brain, compared with peripheral immune cells. Moreover, we assessed the neuroinflammatory impact of high-fat-induced obesity and hypothesised that a MUFA-rich diet might mitigate inflammation despite obesogenic conditions. Toll-like receptor (TLR)2 mediates the inflammation associated with both obesity and AD. Using the TLR2 agonist lipoteichoic acid (LTA), we report that pre-exposure to either palmitic acid (PA) or oleic acid (OA) attenuated cytokine secretion from microglia, but heightened sensitivity to nitric oxide (NO) production. The reduction in cytokine secretion was mirrored in LTA-stimulated macrophages following exposure to PA only, while effects on NO were restricted to OA, highlighting important cell-specific differences. An obesogenic diet over 12 weeks did not induce prominent inflammatory changes in either cortex or hippocampus, irrespective of fat composition. However, we reveal a clear disparity in the effects of MUFA under obesogenic and non-obesogenic conditions.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Palmitic Acid and Oleic Acid Differently Modulate TLR2-Mediated Inflammatory Responses in Microglia and Macrophages

et al. 2022

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“…Urea is a key molecule in the excretion of nitrogenous waste from complex organisms and plays a secondary role in a number of physiological processes, most notably the maintenance of osmotic balance at both cellular and broader physiological levels (1)(2)(3)(4)(5). Urea is primarily excreted in the kidney, where it passes the membrane filter in the glomerulus of the nephron then reabsorbed in the renal tubules.…”

Section: Introductionmentioning

confidence: 99%

Structural characterization of human urea transporters UT-A and UT-B and their inhibition

Chi,

Dietz,

Tang

et al. 2023

Sci. Adv.

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In this study, we present the structures of human urea transporters UT-A and UT-B to characterize them at molecular level and to detail the mechanism of UT-B inhibition by its selective inhibitor, UTB inh -14. High-resolution structures of both transporters establish the structural basis for the inhibitor’s selectivity to UT-B, and the identification of multiple binding sites for the inhibitor will aid with the development of drug lead molecules targeting both transporters. Our study also discovers phospholipids associating with the urea transporters by combining structural observations, native MS, and lipidomics analysis. These insights improve our understanding of urea transporter function at a molecular level and provide a blueprint for a structure-guided design of therapeutics targeting these transporters.

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“…UT-B is believed to be essential for maintaining urea concentration in the central nervous system and may be important in balancing sodium and water in cerebrospinal fluid [ 6 ]. Our previous studies have also suggested a potential role for UT-B in regulation of inflammatory responses in the brain [ 7 ]. Importantly, knockout of UT-B transporters in mice produced significant consequences in the brain, including a substantial increase in urea concentration within the hippocampus and a display of depression-like behavior [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Regional investigation of UT-B urea transporters in the rat brain

Pinki,

Costello,

Stewart

2023

Biochemistry and Biophysics Reports

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Inhibition of Urea Transporter (UT)-B Modulates LPS-Induced Inflammatory Responses in BV2 Microglia and N2a Neuroblastoma Cells

Cited by 8 publications

References 39 publications

Palmitic Acid and Oleic Acid Differently Modulate TLR2-Mediated Inflammatory Responses in Microglia and Macrophages

Palmitic Acid and Oleic Acid Differently Modulate TLR2-Mediated Inflammatory Responses in Microglia and Macrophages

Structural characterization of human urea transporters UT-A and UT-B and their inhibition

Regional investigation of UT-B urea transporters in the rat brain

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