Abstract
Tumor Necrosis Factor (TNF)-α is a proinflammatory cytokine (PIC) and has been implicated in a variety of illness including cardiovascular disease. The current study investigated the inflammatory response trigged by TNFα in both cultured brain neurons and the hypothalamic paraventricular nucleus (PVN), a key cardiovascular relevant brain area, of the Sprague Dawley (SD) rats. Our results demonstrated that TNFα treatment induces a dose- and time-dependent increase in mRNA expression of PICs including Interleukin (IL)-1β and Interleukin-6 (IL6); chemokines including C–C Motif Chemokine Ligand 5 (CCL5) and C–C Motif Chemokine Ligand 12 (CCL12), inducible nitric oxide synthase (iNOS), as well as transcription factor NF-kB in cultured brain neurons from neonatal SD rats. Consistent with this finding, immunostaining shows that TNFα treatment increases immunoreactivity of IL1β, CCL5, iNOS and stimulates activation or expression of NF-kB, in both cultured brain neurons and the PVN of adult SD rats. We further compared mRNA expression of the aforementioned genes in basal level as well as in response to TNFα challenge between SD rats and Dahl Salt-sensitive (Dahl-S) rats, an animal model of salt-sensitive hypertension. Dahl-S brain neurons presented higher baseline levels as well as greater response to TNFα challenge in mRNA expression of CCL5, iNOS and IL1β. Furthermore, central administration of TNFα caused significant higher response in CCL12 in the PVN of Dahl-S rats. The increased inflammatory response to TNFα in Dahl-S rats may be indicative of an underlying mechanism for enhanced pressor reactivity to salt intake in the Dahl-S rat model.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
Data will be available upon reasonable request to the corresponding author.
References
Agudelo LZ et al (2014) Skeletal muscle PGC-1alpha1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 159:33–45. https://doi.org/10.1016/j.cell.2014.07.051
Albert CM, Ma J, Rifai N, Stampfer MJ, Ridker PM (2002) Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation 105:2595–2599. https://doi.org/10.1161/01.cir.0000017493.03108.1c
Basu A, Krady JK, Levison SW (2004) Interleukin-1: a master regulator of neuroinflammation. J Neurosci Res 78:151–156. https://doi.org/10.1002/jnr.20266
Bautista LE, Vera LM, Arenas IA, Gamarra G (2005) Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-alpha) and essential hypertension. J Hum Hypertens 19:149–154. https://doi.org/10.1038/sj.jhh.1001785
Chamarthi B et al (2011) Inflammation and hypertension: the interplay of interleukin-6, dietary sodium, and the renin-angiotensin system in humans. Am J Hypertens 24:1143–1148. https://doi.org/10.1038/ajh.2011.113
Chan CT et al (2012) Reversal of vascular macrophage accumulation and hypertension by a CCR2 antagonist in deoxycorticosterone/salt-treated mice. Hypertension 60:1207–1212. https://doi.org/10.1161/HYPERTENSIONAHA.112.201251
Chang R, Yee KL, Sumbria RK (2017) Tumor necrosis factor alpha Inhibition for Alzheimer’s Disease. J Cent Nerv Syst Dis 9:1179573517709278. https://doi.org/10.1177/1179573517709278
Choi HY, Park HC, Ha SK (2015) Salt sensitivity and hypertension: a paradigm shift from kidney malfunction to vascular endothelial dysfunction. Electrolyte Blood Press 13:7–16. https://doi.org/10.5049/EBP.2015.13.1.7
Cottone S, Vadala A, Vella MC, Mule G, Contorno A, Cerasola G (1998) Comparison of tumour necrosis factor and endothelin-1 between essential and renal hypertensive patients. J Hum Hypertens 12:351–354. https://doi.org/10.1038/sj.jhh.1000596
Dalekos GN, Elisaf MS, Papagalanis N, Tzallas C, Siamopoulos KC (1996) Elevated interleukin-1 beta in the circulation of patients with essential hypertension before any drug therapy: a pilot study. Eur J Clin Investig 26:936–939. https://doi.org/10.1111/j.1365-2362.1996.tb02141.x
Dalekos GN, Elisaf M, Bairaktari E, Tsolas O, Siamopoulos KC (1997) Increased serum levels of interleukin-1beta in the systemic circulation of patients with essential hypertension: additional risk factor for atherogenesis in hypertensive patients? J Lab Clin Med 129:300–308. https://doi.org/10.1016/s0022-2143(97)90178-5
Fan Y, Jiang E, Hahka T, Chen QH, Yan J, Shan Z (2018) Orexin A increases sympathetic nerve activity through promoting expression of proinflammatory cytokines in Sprague Dawley rats. Acta Physiol (Oxford). https://doi.org/10.1111/apha.12963
Frankola KA, Greig NH, Luo W, Tweedie D (2011) Targeting TNF-alpha to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. CNS Neurol Disord Drug Targets 10:391–403. https://doi.org/10.2174/187152711794653751
Hashmat S, Rudemiller N, Lund H, Abais-Battad JM, Van Why S, Mattson DL (2016) Interleukin-6 inhibition attenuates hypertension and associated renal damage in Dahl salt-sensitive rats. Am J Physiol Renal Physiol 311:F555–F561. https://doi.org/10.1152/ajprenal.00594.2015
He P et al (2007) Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice. J Cell Biol 178:829–841. https://doi.org/10.1083/jcb.200705042
Huang BS, Van Vliet BN, Leenen FH (2004) Increases in CSF [Na+] precede the increases in blood pressure in Dahl S rats and SHR on a high-salt diet. Am J Physiol Heart Circ Physiol 287:H1160–H1166. https://doi.org/10.1152/ajpheart.00126.2004
Huang B et al (2016) Renal tumor necrosis factor alpha contributes to hypertension in dahl salt-sensitive rats. Sci Rep 6:21960. https://doi.org/10.1038/srep21960
Huber MJ et al (2017) Increased activity of the orexin system in the paraventricular nucleus contributes to salt-sensitive hypertension. Am J Physiol Heart Circ Physiol 313:H1075–H1086. https://doi.org/10.1152/ajpheart.00822.2016
Jiang E et al (2018) Expression of proinflammatory cytokines is upregulated in the hypothalamic paraventricular nucleus of dahl salt-sensitive hypertensive rats. Front Physiol 9:104. https://doi.org/10.3389/fphys.2018.00104
Kang YM, Ma Y, Zheng JP, Elks C, Sriramula S, Yang ZM, Francis J (2009) Brain nuclear factor-kappa B activation contributes to neurohumoral excitation in angiotensin II-induced hypertension. Cardiovasc Res 82:503–512. https://doi.org/10.1093/cvr/cvp073
Kang YM et al (2010) TNF-alpha in hypothalamic paraventricular nucleus contributes to sympathoexcitation in heart failure by modulating AT1 receptor and neurotransmitters. Tohoku J Exp Med 222:251–263. https://doi.org/10.1620/tjem.222.251
Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT (2018) Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (New York) 4:575–590. https://doi.org/10.1016/j.trci.2018.06.014
Moreira JD et al (2019) Inhibition of microglial activation in rats attenuates paraventricular nucleus inflammation in Galphai2 protein-dependent, salt-sensitive hypertension. Exp Physiol 104:1892–1910. https://doi.org/10.1113/EP087924
Pimenta E, Gaddam KK, Oparil S, Aban I, Husain S, Dell’Italia LJ, Calhoun DA (2009) Effects of dietary sodium reduction on blood pressure in subjects with resistant hypertension: results from a randomized trial. Hypertension 54:475–481. https://doi.org/10.1161/HYPERTENSIONAHA.109.131235
Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S (2011) The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 1813:878–888. https://doi.org/10.1016/j.bbamcr.2011.01.034
Sesso HD, Wang L, Buring JE, Ridker PM, Gaziano JM (2007) Comparison of interleukin-6 and C-reactive protein for the risk of developing hypertension in women. Hypertension 49:304–310. https://doi.org/10.1161/01.HYP.0000252664.24294.ff
Shaftel SS, Griffin WS, O’Banion MK (2008) The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J Neuroinflamm 5:7. https://doi.org/10.1186/1742-2094-5-7
Shi P et al (2010) Brain microglial cytokines in neurogenic hypertension. Hypertension 56:297–303. https://doi.org/10.1161/HYPERTENSIONAHA.110.150409
Shi Z et al (2011) Inflammatory cytokines in paraventricular nucleus modulate sympathetic activity and cardiac sympathetic afferent reflex in rats. Acta Physiol (Oxford) 203:289–297. https://doi.org/10.1111/j.1748-1716.2011.02313.x
Sriramula S, Cardinale JP, Francis J (2013) Inhibition of TNF in the brain reverses alterations in RAS components and attenuates angiotensin II-induced hypertension. PLoS ONE 8:e63847. https://doi.org/10.1371/journal.pone.0063847
Stefferl A, Hopkins SJ, Rothwell NJ, Luheshi GN (1996) The role of TNF-alpha in fever: opposing actions of human and murine TNF-alpha and interactions with IL-beta in the rat. Br J Pharmacol 118:1919–1924. https://doi.org/10.1111/j.1476-5381.1996.tb15625.x
Tang P, Chong L, Li X, Liu Y, Liu P, Hou C, Li R (2014) Correlation between serum RANTES levels and the severity of Parkinson’s disease. Oxid Med Cell Longev 2014:208408. https://doi.org/10.1155/2014/208408
Wainford RD, Carmichael CY, Pascale CL, Kuwabara JT (2015) Galphai2-protein-mediated signal transduction: central nervous system molecular mechanism countering the development of sodium-dependent hypertension. Hypertension 65:178–186. https://doi.org/10.1161/HYPERTENSIONAHA.114.04463
Wei SG, Zhang ZH, Beltz TG, Yu Y, Johnson AK, Felder RB (2013) Subfornical organ mediates sympathetic and hemodynamic responses to blood-borne proinflammatory cytokines. Hypertension 62:118–125. https://doi.org/10.1161/HYPERTENSIONAHA.113.01404
Wei SG, Yu Y, Zhang ZH, Felder RB (2015) Proinflammatory cytokines upregulate sympathoexcitatory mechanisms in the subfornical organ of the rat. Hypertension 65:1126–1133. https://doi.org/10.1161/HYPERTENSIONAHA.114.05112
Weinberger MH (1996) Salt sensitivity of blood pressure in humans. Hypertension 27:481–490. https://doi.org/10.1161/01.hyp.27.3.481
Willerson JT, Ridker PM (2004) Inflammation as a cardiovascular risk factor. Circulation 109:II2–II10. https://doi.org/10.1161/01.CIR.0000129535.04194.38
Yilmaz R, Akoglu H, Altun B, Yildirim T, Arici M, Erdem Y (2012) Dietary salt intake is related to inflammation and albuminuria in primary hypertensive patients. Eur J Clin Nutr 66:1214–1218. https://doi.org/10.1038/ejcn.2012.110
Yoshida S et al (2014) Infliximab, a TNF-alpha inhibitor, reduces 24-h ambulatory blood pressure in rheumatoid arthritis patients. J Hum Hypertens 28:165–169. https://doi.org/10.1038/jhh.2013.80
Yuste JE, Tarragon E, Campuzano CM, Ros-Bernal F (2015) Implications of glial nitric oxide in neurodegenerative diseases. Front Cell Neurosci 9:322. https://doi.org/10.3389/fncel.2015.00322
Zhang ZH, Wei SG, Francis J, Felder RB (2003) Cardiovascular and renal sympathetic activation by blood-borne TNF-alpha in rat: the role of central prostaglandins. Am J Physiol Regul Integr Comp Physiol 284:R916-927. https://doi.org/10.1152/ajpregu.00406.2002
Zubcevic J et al (2013) Nucleus of the solitary tract (pro)renin receptor-mediated antihypertensive effect involves nuclear factor-kappaB-cytokine signaling in the spontaneously hypertensive rat. Hypertension 61:622–627. https://doi.org/10.1161/HYPERTENSIONAHA.111.199836
Acknowledgements
This work was supported by NIH R15HL150703 (Shan) and Portage Health Foundations Mid-Career (Shan).
Author information
Authors and Affiliations
Contributions
HG and ZS designed the experiments and participated in data collection and analysis, YF participated in data analysis and Figure editing, JB and ZS wrote the paper. EJ, QC and BC supervised HG for her research and participated in helpful discussion and data analysis. All Authors read and approved the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
There are no conflicts of interest to report.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Gao, H., Bigalke, J., Jiang, E. et al. TNFα Triggers an Augmented Inflammatory Response in Brain Neurons from Dahl Salt-Sensitive Rats Compared with Normal Sprague Dawley Rats. Cell Mol Neurobiol 42, 1787–1800 (2022). https://doi.org/10.1007/s10571-021-01056-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-021-01056-9