Are T Cells to Blame for Cognitive Impairment Caused by Hypertension?

Hypertension has long been linked to cognitive impairment, but physical strain on small blood vessels in the brain might not be the only explanation. In the December 4 Nature Neuroscience, scientists led by Monica Santisteban and Costantino Iadecola at the Weill Cornell Medical College in New York reported that in a mouse model of hypertension, interleukin-17 constricts blood flow, causing the mice to become forgetful. The cytokine stems blood flow in two ways, the researchers say. In the blood, it binds endothelial cells, preventing vessels from dilating. In the meninges, IL-17 made by T cells signals perivascular macrophages to release reactive oxygen species, damaging nearby blood vessels and limiting neurovascular coupling. Both actions dulled learning and memory. Depleting the T cells, the macrophages, or the IL-17 receptor restored neurovascular function and cognition. “Lowering blood pressure is critical for maintaining the health of the heart and kidneys and for stroke prevention, but we believe preventing hypertensive cognitive impairment may require modulation of the immune response set off by IL-17,” said Iadecola.

  • In hypertensive mice, IL-17 seeps into the parenchyma.
  • It binds perivascular macrophages, restricting blood flow.
  • In vessels, the cytokine also binds endothelial cells, blocking vasodilation.
  • The upshot: poor memory.

“This study nicely demonstrates that neurovascular and cognitive dysfunction associated with salt-sensitive hypertension is mediated by two distinct mechanisms involving IL-17 acting on cerebral endothelium and on parenchymal border macrophages,” wrote Jonathan Kipnis and Steffen Storck, both at the Washington University School of Medicine in St. Louis (comment below).

Marco Prinz of the University of Freiburg in Germany called the research elegant and timely. “The power of this study is the impressive armamentarium of tools that shows, for the first time, that CNS-associated macrophages … recognize IL-17 produced by dural T cells and thereby modulate cognitive decline.”

To study how high blood pressure harms the brain, first author Santisteban, who is now at Vanderbilt University in Nashville, subcutaneously implanted a pellet containing deoxycorticosterone acetate (DOCA) into mice, then added a little salt to their drinking water. DOCA prevents sodium excretion by the kidneys, forcing it to build up in the blood. The osmotic pressure increases blood volume, which signals angiotensin in the brain to release vasoconstrictive hormones into the periphery, an effort to squeeze out the excess fluid. This drives up blood pressure as soon as three days after DOCA implantation. Iadecola called these mice the most clinically relevant model of hypertension because excess salt intake is a common cause of high blood pressure in people.

Through a cranial window in the somatosensory cortex, Santisteban used laser-Dopler flowmetry to measure blood flow induced in two ways: endothelial vasodilation, stemming from endothelial cells pumping out nitric oxide in response to injection of acetylcholine; and functional hyperemia (aka neurovascular coupling), where neurons release nitric oxide after the mouse’s whiskers are tickled. Both types of blood flow were diminished 10 days after DOCA implantation (image below). Hypertensive mice also had trouble distinguishing new objects from old ones and finding their way out of a circular maze.

No Flow. While a cerebral blood vessel from a wild-type mouse (top left) expands to increase blood flow after being bathed in acetylcholine (top right), a vessel from a hypertensive mouse (bottom left) is unresponsive (bottom right). [Courtesy of Santisteban et al., Nature Neuroscience, 2023.]

IL-17 causes hypertension in mice, and Iadecola had seen an uptick in the cytokine in the plasma of mice fed a high-salt diet, even when they didn’t have high blood pressure (Madhur et al., 2010; Itani et al., 2016; Jan 2018 news). To see if IL-17 mediated the cognitive deficit in DOCA animals, Santisteban knocked out the IL-17 gene. In these mice, cerebral blood flow was normal, and their memories stayed sharp, despite their high blood pressure, indicating the cytokine played a role in both.

What cells mediated the IL-17 effect? Since endothelial cells regulate blood pressure and are exposed to IL-17 circulating in vessels, the scientists selectively knocked out their IL-17 receptors, then induced hypertension with DOCA and salt. These mice had normal vasodilation and they recognized novel objects better than controls with a full complement of IL-17 receptors. However, functional hyperemia in the IL-17R knockouts still flagged, and the mice struggled to escape the circular maze. This partial restoration of function and memory suggests that some other cells might contribute to the IL-17 response.

In the brain, border-associated macrophages (BAMs) that hug vascular endothelial cells also express IL-17 receptors (Van Hove et al., 2019). Might they limit hyperemia?  Indeed, depleting BAMs, or selectively knocking out IL-17R in those cells, restored this type of vasodilation, but not endothelial vasodilation. Still, both working and spatial memory improved.

Two Sides to IL-17. The authors postulate that IL-17 (blue diamonds) dampens cerebral blood flow two ways. Inside vessels, it binds endothelial cells (EC), reducing their nitric oxide (NO) production and preventing them from dilating blood vessels. In the brain, T cells (green circles) in the dura make IL-17, which slips through damaged arachnoid membranes to reach perivascular macrophages. The latter then unleashes reactive oxygen species, which damage the vessels. [Courtesy of Santisteban et al., Nature Neuroscience, 2023.]

How do BAMs influence neuron signaling and blood flow? These macrophages contain high levels of enzymes that can generate reactive oxygen species, which can damage the smooth muscle and endothelial cells of nearby blood vessels (image above). In wild-type hypertensive mice, Santisteban found an uptick in ROS within the macrophages, but not in hypertensive BAM IL-17R knockouts, suggesting that IL-17 induces ROS. The authors believe these ROS disrupt blood flow.

Because BAMs are not in direct contact with the blood, the scientists suspected that the IL-17 activating those cells came from somewhere within the brain. They found IL-17 mRNA only within the dura, where expression increased after DOCA-salt treatment. Flow cytometry traced the source of this cytokine to dural T cells. Dura taken from hypertensive mice had no more of these T cells than did wild-type dura, but more of the cells made IL-17 (image below). The researchers suspect that the cytokine slips from the dura through the arachnoid barrier, as it was damaged in DOCA mice, into the perivascular space to bind BAMs (image above). Depleting all T cells, or just those in the dural, restored functional hyperemia and improved working and spatial memory.

Interleukin Eruption. More T-cells express IL-17 (magenta) in the dura after mice are given DOCA and salt water. [Courtesy of Santisteban et al., Nature Neuroscience, 2023.]

All told, Iadecola concluded that IL-17-producing T cells in the dura drive neurovascular problems and cognitive impairment associated with hypertension. This isn’t the first time dural T cell IL-17 has been implicated in memory. Previously, scientists reported that when released from γδT cells, the cytokine stimulated the production of brain-derived neurotrophic growth factor in wild-type mice, improving plasticity and short-term memory (Oct 2019 news). Why would it improve memory in some mice but not others?  Iadecola chalks that up to different mouse models and a balance of IL-17. “Every molecule in certain levels is good, but if you have too much of it, or if you have a convergence of pathogenic factors, things go bad,” he said.

David Harrison at Vanderbilt called Iadecola’s findings important, noting there are drugs available to suppress IL-17 (comment below). Secukinumab, ixekizumab, and brodalumab are FDA-approved to treat plaque psoriasis and psoriatic arthritis, skin and joint conditions caused by too much IL-17. Researchers in Greece are recruiting for a clinical trial to study the effects of secukinumab on vascular function in people with psoriasis.—Chelsea Weidman Burke

Comments

  1. This elegant study nicely demonstrates that neurovascular and cognitive dysfunction associated with salt-sensitive hypertension is mediated by two distinct mechanisms, involving IL-17 acting on cerebral endothelium and on parenchymal border (perivascular and leptomeningeal) macrophages that sample CSF and regulate its dynamics (Drieu et al., 2022).

    Employing a virus that targets CNS endothelium, the authors deleted IL-17 receptors from brain vasculature and rescued neurovascular dysfunction in their hypertension model. Using their novel Mrc1-CreERT2 mouse, the authors deleted IL-17 receptors specifically from parenchymal border macrophages, which rescued cognitive dysfunction.

    Moreover, the authors suggest that Il-17 produced by γδ T cells in the dura signals to parenchymal border macrophages in the brain. Intraventricular delivery of anti-TCRγδ antibodies efficiently depleted dural γδ T cells.

    These data, along with other data from our (Rustenhoven, et al., 2021; Alves de Lima, et al., 2020; Louveau et al., 2015), and other laboratories (Ribeiro et al., 2019), propose that there is bidirectional communication between the brain and dura. Interestingly, the authors suggest that changes in the arachnoid barrier could allow cytokine penetration into the brain. Recently, this understudied brain barrier has received more attention from the scientific community (Derk et al., 2023; Pietilä et al., 2023), but we are just beginning to understand the molecular mechanisms and pathways that govern barrier and signaling function or the arachnoid. Further studies are needed to fully understand how molecules cross that barrier, and what implications that has for brain diseases.

    References:

    Drieu A, Du S, Storck SE, Rustenhoven J, Papadopoulos Z, Dykstra T, Zhong F, Kim K, Blackburn S, Mamuladze T, Harari O, Karch CM, Bateman RJ, Perrin R, Farlow M, Chhatwal J, Dominantly Inherited Alzheimer Network, Hu S, Randolph GJ, Smirnov I, Kipnis J. Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid. Nature. 2022 Nov;611(7936):585-593. Epub 2022 Nov 9 PubMed.

    Rustenhoven J, Drieu A, Mamuladze T, de Lima KA, Dykstra T, Wall M, Papadopoulos Z, Kanamori M, Salvador AF, Baker W, Lemieux M, Da Mesquita S, Cugurra A, Fitzpatrick J, Sviben S, Kossina R, Bayguinov P, Townsend RR, Zhang Q, Erdmann-Gilmore P, Smirnov I, Lopes MB, Herz J, Kipnis J. Functional characterization of the dural sinuses as a neuroimmune interface. Cell. 2021 Jan 18; PubMed.

    Alves de Lima K, Rustenhoven J, Da Mesquita S, Wall M, Salvador AF, Smirnov I, Martelossi Cebinelli G, Mamuladze T, Baker W, Papadopoulos Z, Lopes MB, Cao WS, Xie XS, Herz J, Kipnis J. Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons. Nat Immunol. 2020 Nov;21(11):1421-1429. Epub 2020 Sep 14 PubMed.

    Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015 Jul 16;523(7560):337-41. Epub 2015 Jun 1 PubMed.

    Ribeiro M, Brigas HC, Temido-Ferreira M, Pousinha PA, Regen T, Santa C, Coelho JE, Marques-Morgado I, Valente CA, Omenetti S, Stockinger B, Waisman A, Manadas B, Lopes LV, Silva-Santos B, Ribot JC. Meningeal γδ T cell-derived IL-17 controls synaptic plasticity and short-term memory. Sci Immunol. 2019 Oct 11;4(40) PubMed.

    Derk J, Como CN, Jones HE, Joyce LR, Kim S, Spencer BL, Bonney S, O'Rourke R, Pawlikowski B, Doran KS, Siegenthaler JA. Formation and function of the meningeal arachnoid barrier around the developing mouse brain. Dev Cell. 2023 Apr 24;58(8):635-644.e4. Epub 2023 Mar 29 PubMed.

    Pietilä R, Del Gaudio F, He L, Vázquez-Liébanas E, Vanlandewijck M, Muhl L, Mocci G, Bjørnholm KD, Lindblad C, Fletcher-Sandersjöö A, Svensson M, Thelin EP, Liu J, van Voorden AJ, Torres M, Antila S, Xin L, Karlström H, Storm-Mathisen J, Bergersen LH, Moggio A, Hansson EM, Ulvmar MH, Nilsson P, Mäkinen T, Andaloussi Mäe M, Alitalo K, Proulx ST, Engelhardt B, McDonald DM, Lendahl U, Andrae J, Betsholtz C. Molecular anatomy of adult mouse leptomeninges. Neuron. 2023 Dec 6;111(23):3745-3764.e7. Epub 2023 Sep 29 PubMed.

    View all comments by Jonathan Kipnis View all comments by Steffen Storck

  2. We discovered about 15 years ago that IL-17, a key T-cell-derived cytokine, contributes to hypertension. Subsequently, others confirmed this. Hypertension is clearly associated with cognitive dysfunction. Indeed, this group has made an enormous contribution to the field by establishing the concept of the neurovascular unit, which links vascular function and perfusion to the metabolic needs of brain regions. Since hypertension affects vascular, and particularly endothelial function, it makes sense that it would alter the function of the neurovascular unit.

    The new finding in this study is that IL-17A, released from meningeal T cells, acts on a special population of macrophages, which in turn release reactive oxygen species that impair vascular function. This is very important, because there are ways to modulate IL-17 levels in humans.

    A major challenge is that studies like this, and those that we do, always begin at the onset of hypertension, or at best intervene after a few days or weeks later. In humans, hypertension usually exists for years to decades before it is treated, so there is often irreversible organ damage. For example, we know that vessels become narrowed, scarred, and ultimately disappear in hypertension, and this likely isn’t reversible.

    I am surprised that the authors didn’t see blunted hypertension in mice lacking IL-17A, because we and others have.

    Cytokines usually work in concert, so it is possible that other cytokines also contribute.

    View all comments by David Harrison
    • User Profile Image Marco Prinz
      University Hospital Freiburg, Institute of Neuropathology
    • Posted:

    This is a very elegant, timely, and superb study by the Iadecola lab. It was not known by what mechanisms hypertension causes cognitive impairment. Here, the authors used a sophisticated, salt-sensitive model to decipher the underlying mechanistical steps of this pathophysiological condition. The power of this study is the impressive armamentarium of tools that show, for the first time, that CNS-associated macrophages (CAMs, or alternatively border-associated macrophages, aka BAMs) recognize IL-17 produced by dural T cells and thereby modulate cognitive decline.

    I can only congratulate the authors on the plethora of converging methods to demonstrate this. One special highlight is the generation of tamoxifen-inducible, CAM-specific, Mrc-1 ERT2 Cre mice that nicely supplements the exiting pool of new genetic tools to dissect the function role of tissue resident macrophages in the CNS (e.g., Masuda et al., 2022). 

    References:

    Masuda T, Amann L, Monaco G, Sankowski R, Staszewski O, Krueger M, Del Gaudio F, He L, Paterson N, Nent E, Fernández-Klett F, Yamasaki A, Frosch M, Fliegauf M, Bosch LF, Ulupinar H, Hagemeyer N, Schreiner D, Dorrier C, Tsuda M, Grothe C, Joutel A, Daneman R, Betsholtz C, Lendahl U, Knobeloch KP, Lämmermann T, Priller J, Kierdorf K, Prinz M. Specification of CNS macrophage subsets occurs postnatally in defined niches. Nature. 2022 Apr;604(7907):740-748. Epub 2022 Apr 20 PubMed.

    View all comments by Marco Prinz

  4. Undoubtedly, the new study by Drs. Santisteban and Iadecola is conclusive, deep, and—agreeing with Drs. Kipnis and Storck—elegant.

    However, it is as relevant for human health as the DOCA hypertension model holds for human chronic hypertension.

    Kipnis and Storck point out that there is (undoubtedly) a bidirectional communication between dura and brain—but whether this validates the new data in terms of their human health relevance remains to be seen.

    With this new result, it will be imperative to conduct translational studies to validate the proposed mechanism for its human health relevance. These could include proteomics studies, the systemic proteome clearly being favored based on feasibility. They also include human genetics studies including Mendelian randomization for IL17-signaling, in order to compare normal versus gain- versus loss-of-function alleles, patients with and without hypertension, and then, as critical readout, incidence of MCI and dementia.

    I am also endorsing the thoughtful comment by Dr. Harrison.

    View all comments by Wolfgang Liedtke

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References

News Citations

  1. Gut Immune Cells, not Blood Pressure, Blamed for Salt’s Effect on Brain
  2. Do Immune Cells in the Meninges Help with … Memory?

Paper Citations

  1. Madhur MS, Lob HE, McCann LA, Iwakura Y, Blinder Y, Guzik TJ, Harrison DG. Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction. Hypertension. 2010 Feb;55(2):500-7. Epub 2009 Dec 28 PubMed.
  2. Itani HA, McMaster WG Jr, Saleh MA, Nazarewicz RR, Mikolajczyk TP, Kaszuba AM, Konior A, Prejbisz A, Januszewicz A, Norlander AE, Chen W, Bonami RH, Marshall AF, Poffenberger G, Weyand CM, Madhur MS, Moore DJ, Harrison DG, Guzik TJ. Activation of Human T Cells in Hypertension: Studies of Humanized Mice and Hypertensive Humans. Hypertension. 2016 Jul;68(1):123-32. Epub 2016 May 23 PubMed.
  3. Van Hove H, Martens L, Scheyltjens I, De Vlaminck K, Pombo Antunes AR, De Prijck S, Vandamme N, De Schepper S, Van Isterdael G, Scott CL, Aerts J, Berx G, Boeckxstaens GE, Vandenbroucke RE, Vereecke L, Moechars D, Guilliams M, Van Ginderachter JA, Saeys Y, Movahedi K. A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat Neurosci. 2019 Jun;22(6):1021-1035. Epub 2019 May 6 PubMed.

External Citations

  1. clinical trial

Further Reading

No Available Further Reading

Primary Papers

  1. Santisteban MM, Schaeffer S, Anfray A, Faraco G, Brea D, Wang G, Sobanko MJ, Sciortino R, Racchumi G, Waisman A, Park L, Anrather J, Iadecola C. Meningeal interleukin-17-producing T cells mediate cognitive impairment in a mouse model of salt-sensitive hypertension. Nat Neurosci. 2024 Jan;27(1):63-77. Epub 2023 Dec 4 PubMed.

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