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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  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 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

  3. 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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