Abstract
Hypertension (HTN), a disease afflicting over one billion individuals worldwide, is a leading cause of cognitive impairment, the mechanisms of which remain poorly understood. In the present study, in a mouse model of HTN, we find that the neurovascular and cognitive dysfunction depends on interleukin (IL)-17, a cytokine elevated in individuals with HTN. However, neither circulating IL-17 nor brain angiotensin signaling can account for the dysfunction. Rather, IL-17 produced by T cells in the dura mater is the mediator released in the cerebrospinal fluid and activating IL-17 receptors on border-associated macrophages (BAMs). Accordingly, depleting BAMs, deleting IL-17 receptor A in brain macrophages or suppressing meningeal T cells rescues cognitive function without attenuating blood pressure elevation, circulating IL-17 or brain angiotensin signaling. Our data unveil a critical role of meningeal T cells and macrophage IL-17 signaling in the neurovascular and cognitive dysfunction in a mouse model of HTN.
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Acknowledgements
This work was supported by grants from the National Institutes of Health (nos. R37-NS089323 and R01-NS095441 to C.I. and K22-NS123507 to M.M.S.), as well as the Leon Levy Fellowship in Neuroscience (to M.M.S.). The support from the Feil Family Foundation is gratefully acknowledged. Figure schematics were created with BioRender.com.
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M.M.S, S.S., A.A., G.F., D.B.L. and R.S. conducted the experiments and performed the data analysis. G.W. performed the NO measurement of vessels ex vivo. M.J.S. performed the RNAscope experiments and assisted in mouse breeding and genotyping. G.R. performed the RT–qPCR. A.W. provided IL-17RAflox/flox mice and edited the manuscript. L.P., J.A. and C.I. supervised the research. M.M.S. and C.I. provided funding and wrote the manuscript.
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Extended data
Extended Data Fig. 1 Physiological parameters at 21 days of DOCA-salt HTN.
(A-B) Tissue sodium (A) and potassium (B) content was assessed by inductively coupled plasma – atomic emission spectrometry (ICP-AES)75,76. Intergroup differences analyzed by unpaired two-tailed t-test for each organ, n = 6–10 mice/group as shown. (C-D) BBB permeability (D) assessed by brain extravasation of 3 kDa FITC-dextran (C) quantified by spectrophotometry in brain homogenates revealed no impairment during DOCA-salt hypertension (n = 5–8). (E-F) DOCA-salt HTN does not impair resting CBF assessed quantitatively by arterial spin label (ASL)-MRI (control (E) n = 10 mice, DOCA (F) n = 9 mice) at 21 days of treatment in the hippocampus (Hipp), cortex (Ctx), amygdala (Amyg), caudate putamen (CP), thalamus (Thal), or hypothalamus (Hypoth). Intergroup differences analyzed by two-way ANOVA with Tukey’s multiple comparisons test. (G) IL17-GFP+ neutrophils were not changed by DOCA-salt in peripheral blood mononuclear cells (PBMC) or in the dura. n = 4/group.
Extended Data Fig. 2 Systolic blood pressure measured by tail-cuff plethysmography.
Systolic blood pressure (SBP) was assessed twice per week in all control and DOCA-salt mice of the following groups: (A) wild-type (WT, n = 10 mice) and IL17-deficient (IL17KO, n = 6 mice) mice, (B) WTBR1 (n = 5 mice/group) and IL17RA brain endothelial cell knockout (IL17RAbECKO, n = 6 mice/group), (C) mice treated with vehicle (PBS) or clodronate (CLO)-containing liposomes (n = 10 mice/group), (D and E) bone marrow chimeras (n = 5 mice/group), and (F) i.c.v. saline or losartan (n = 6 mice/group). Intergroup differences analyzed by two-way repeated measures ANOVA with Tukey’s multiple comparisons test.
Extended Data Fig. 3 Cerebral endothelial cell specific Cre delivery with AAV-BR1-iCre.
(A) AAV-BR1-iCre delivery in Ai14-ROSAtdTomato reporter mice demonstrates (B) widespread TdTomato (TdTM) expression in cerebral vessels. Scale bar: 500μm. (C) Specifically, we observed a 90–95% endothelial viral transduction in vessels less than 20μm (n = 5 mice, 110 vessels per mouse). (D) Representative images of TdTM expression in CD31+ endothelial cells. Scale bar: 150μm. (E) Quantification of genomic IL-17RA deletion in EC and MG (n = 4 mice/group). Intergroup differences analyzed by two-way ANOVA with Tukey’s multiple-comparison test.
Extended Data Fig. 4 Brain macrophages depletion with clodronate and ROS measurement.
(A) i.c.v. clodronate depletes brain macrophages for 21 days, and (B) initially depletes dura macrophages, but they are fully restored within 21 days. n = 3–7 mice/group as shown. Intergroup differences analyzed by one-way ANOVA with Tukey’s multiple-comparison test. (C) DOCA-salt does not increase BAM ROS IL17RA-/-→WT chimeras (control n = 3 mice, DOCA n = 4 mice), or (D) in WT mice treated with FTY720 (n = 4 mice/group). Intergroup differences analyzed by two-way ANOVA with Tukey’s multiple comparisons test.
Extended Data Fig. 5 Novel Mrc1CreERT2/+ mouse.
(A) Schematic of CNS macrophage compartments. (B) Illustration of the experimental procedure for intracerebroventricular (i.c.v.) FITC-Dextran injection and analysis of adult Mrc1+/+ or Mrc1CreERT2/+. (C-E) Immunofluorescence images reveals FITC-Dextran (green) (c) in BAMs (CD206 + , red) in perivascular macrophages (pvMΦ) and pial MΦ (D) and dural MΦ (E) compartments in the cortex of adult Mrc1+/+ or Mrc1CreERT2/+ mice. CD31+ blood vessels shown in cyan. Scale bars: 20 μm. (F) Quantification of pvMΦ, pial MΦ and dural MΦ in Mrc1+/+ (n = 4 mice) or Mrc1CreERT2/+ (n = 6 mice for of pvMΦ and pial MΦ, n = 5 mice for dural MΦ). Data shown as mean ± SEM; intergroup differences analyzed by two-way ANOVA with Bonferroni’s multiple comparison test. (G) CD206 surface expression levels on individual FITC-Dextran cells (pvMΦ Mrc1+/+ n = 586 cells, Mrc1CreERT2/+ n = 676 cells; pial Mrc1+/+ n = 235 cells, Mrc1CreERT2/+ n = 340 cells; dural Mrc1+/+ n = 1780 cells, Mrc1CreERT2/+ n = 1871 cells. Mrc1+/+ n = 4 mice, Mrc1CreERT2/+ n = 6 mice for of pvMΦ and pial MΦ, n = 5 mice for dural MΦ; 10 images per mouse per compartment, all cells within each image were analyzed). Intergroup differences analyzed by unpaired two-tailed Mann Whitney test; lines in violin plot indicate median and quartiles.
Extended Data Fig. 6 Novel Mrc1CreERT2/+ mouse.
(A) Experimental procedure for tamoxifen administration (TAM) and analysis of adult Mrc1+/+R26tdTM/+ or Mrc1CreERT2/+R26tdTM/+ mice. (B-D) Immunofluorescence images reveal tdTM+ (red) in CD206+ BAM (green) in perivascular macrophages (pvMΦ) (B), pial MΦ (c), and dural MΦ (D). CD31+ blood vessels shown in cyan. Scale bars: 20 μm. (E) TdTM expression was no observed in microglia (IBA1+, green) of adult Mrc1CreERT2/+R26tdTM/+ mice. Scale bars: 20 μm. (F) Quantification of recombination efficacy in pvMΦ, pial MΦ, and dural MΦ, as well as microglia in Mrc1+/+R26tdTM/+ and Mrc1CreERT2/+R26tdTM/+ mice. Data shown as mean ± SEM; Mrc1+/+R26tdTM/+ n = 5 mice per compartment except n = 3 mice for dura; and Mrc1CreERT2/+R26tdTM/+ n = 6 mice for pvMΦ and pial, and n = 5 mice for dural and microglia. (G) Experimental procedure for tamoxifen administration and analysis of Mrc1CreERT2/+ x IL17RAflox/flox mice. (H) Representative image of cerebral blood vessel stained for CD31 (yellow, IHC), Mrc1 (cyan, RNAscope) and IL17RA (magenta, RNAscope). Blood vessel shows one IL17RA- BAM and one IL17RA + BAM. This identification strategy was used for quantification of IL17RA deletion in Mrc1CreERT2/+ x IL17RAflox/flox mice. Scale bars: 10 μm.
Extended Data Fig. 7 Total numbers of cells obtained by flow cytometry in dura.
Total numbers of cells obtained by flow cytometry from control (n = 14 mice) and DOCA (n = 17 mice) dura samples. (A) Total CD4 cells. (B) Total Th17 cells. (C) Total γδT cells. (D)Total γδT17 cells.
Extended Data Fig. 8 Markers of neuroinflammation in neocortex and hippocampus.
(A-B) Selected inflammatory gene expression assessed by qPCR was not altered in cortex (A) (control n = 15 mice; DOCA n = 12 mice) or hippocampus (B) of DOCA-salt mice (control n = 10 mice; DOCA n = 8 mice). Intergroup differences analyzed by two-way ANOVA with Tukey’s multiple comparison test. (C) Iba1+ microglia and (D) GFAP+ astrocyte area was not altered in the hippocampus of DOCA-salt (control n = 3 mice, DOCA n = 4 mice). Intergroup differences analyzed by unpaired two-tailed t-test. Scale bars: 150 μm.
Extended Data Fig. 9 Brain Agtr1a and renal Ren1 mRNA expression.
Brain Agtr1a and renal Ren1 mRNA expression in (A) IL-17KO (brain n = 6 mice/group, kidney n = 5 mice/group) and (B) vehicle and FTY720-treated control and DOCA-salt mice (n = 4–8 mice/group as shown). Intergroup differences analyzed by unpaired two-tailed t-test (A) or two-way ANOVA with Tukey’s multiple comparison test (B).
Extended Data Fig. 10 Summary diagram.
Summary of the mechanisms by which DOCA-salt hypertension alters neurovascular and cognitive function in mice. These effects are mediated by concurring actions of IL17 acting on IL17RA on different cells types on both sides of the BBB. In the circulation, IL-17 produced by T-cells acts on cerebral endothelial IL-17RA to reduce NO production leading to suppression of endothelial vasoactivity without affecting the increase in CBF induced by neural activity. In the brain, IL-17 produced by dura T-cells acts on IL-17RA on BAM to induce vascular oxidative stress and suppression of functional hyperemia with minimal effects on endothelial function.
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Santisteban, M.M., Schaeffer, S., Anfray, A. et al. Meningeal interleukin-17-producing T cells mediate cognitive impairment in a mouse model of salt-sensitive hypertension. Nat Neurosci 27, 63–77 (2024). https://doi.org/10.1038/s41593-023-01497-z
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DOI: https://doi.org/10.1038/s41593-023-01497-z
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