Drugs Modulating CD4+ T Cells Blood–Brain Barrier Interaction in Alzheimer’S Disease
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pharmaceutics Review Drugs Modulating CD4+ T Cells Blood–Brain Barrier Interaction in Alzheimer’s Disease Norwin Kubick 1 , Patrick C. Henckell Flournoy 2, Ana-Maria Enciu 3 , Gina Manda 3 and Michel-Edwar Mickael 4,5,* 1 Institute of Biochemistry, Molecular Cell Biology, University Clinic Hamburg-Eppendorf, 20251 Hamburg, Germany; [email protected] 2 PM Research Center, 20 Kaggeholm, Ekerö, 178 54 Stockholm, Sweden; pfl[email protected] 3 Victor Babes National Institute of Pathology, 050096 Bucures, ti, Romania; [email protected] (A.-M.E.); [email protected] (G.M.) 4 Bevill Biomedical Sciences Research Building, UAB Birmingham, AL 35294-2170, USA 5 Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, ul. Postepu 36A, Jastrz˛ebiec,05-552 Magdalenka, Poland * Correspondence: [email protected]; Tel.: +46-730-639-459 Received: 7 August 2020; Accepted: 14 September 2020; Published: 16 September 2020 Abstract: The effect of Alzheimer’s disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. CD4+ T cells could both exacerbate and reduce AD symptoms based on their infiltrating subpopulations. Proinflammatory subpopulations such as Th1 and Th17 constitute a major source of proinflammatory cytokines that reduce endothelial integrity and stimulate astrocytes, resulting in the production of amyloid β. Anti-inflammatory subpopulations such as Th2 and Tregs reduce inflammation and regulate the function of Th1 and Th17. Recently, pathogenic Th17 has been shown to have a superior infiltrating capacity compared to other major CD4+ T cell subpopulations. Alzheimer’s drugs such as donepezil (Aricept), rivastigmine (Exelon), galantamine (Razadyne), and memantine (Namenda) are known to play an important part in regulating the mechanisms of the neurotransmitters. However, little is known about the effect of these drugs on CD4+ T cell subpopulations’ infiltration of the brain during AD. In this review, we focus on understanding the influence of AD drugs on CD4+ T cell subpopulation interactions with the BBB in AD. While current AD therapies improve endothelial integrity and reduce astrocytes activations, they vary according to their influence on various CD4+ T cell subpopulations. Donepezil reduces the numbers of Th1 but not Th2, Rivastigmine inhibits Th1 and Th17 but not Th2, and memantine reduces Th1 but not Treg. However, none of the current AD drugs is specifically designed to target the dysregulated balance in the Th17/Treg axis. Future drug design approaches should specifically consider inhibiting CD4+ Th17 to improve AD prognosis. Keywords: Alzheimer; blood brain barrier; CD4+ T cells; migration; Th17 1. Who Are CD4+ T Cells? Peripheral CD4+ T cells constitute a major branch of adaptive immunity. These cells are produced in the bone marrow and emigrate to the thymus and then to the periphery where they continue to differentiate. Major peripheral CD4+ T cell subpopulations could be clustered into two main groups: (i) helper subpopulations such as Th1, Th2 and Th17; and (ii) regulatory subpopulations such as Tregs [1,2]. Each type of these subpopulations is classically governed by a master regulator. For example, Th1 is governed by Tbx21, while Th2 is controlled by Gata3. Th17 master regulator is RoRc and Treg is controlled by FoxP3 expression. CD4+ T cell subpopulations could be characterized Pharmaceutics 2020, 12, 880; doi:10.3390/pharmaceutics12090880 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2020, 12, 880 2 of 18 Pharmaceutics 2020, 12, x 2 of 18 based on their cytokines production. For example, Th1 cells are known to produce IL-2 and IFN-γ based on their cytokines production. For example, Th1 cells are known to produce IL-2 and IFN-γ as as well as TNFα, making them proinflammatory and pathogenic, while Th2 cells produce IL-4, IL-5, well as TNFα, making them proinflammatory and pathogenic, while Th2 cells produce IL-4, IL-5, and and IL-13, giving them the ability to neutralize Th1 response. Th17 cells produce IL-17A and IL-17F. IL-13, giving them the ability to neutralize Th1 response. Th17 cells produce IL-17A and IL-17F. Tregs Tregs produce IL-10 and they can inhibit other CD4+ T cells. Th17 and Treg are controlled by a similar produce IL-10 and they can inhibit other CD4+ T cells. Th17 and Treg are controlled by a similar transcription network, thus they form the Th17/Treg axis [3]. It is important to note that CD4+ T cells transcription network, thus they form the Th17/Treg axis [3]. It is important to note that CD4+ T cells could be programmable from one state to another according to their environmental circumstances. could be programmable from one state to another according to their environmental circumstances. For example, Th17 could re-differentiate into a more pathogenic phenotype known as Th17(Th1-like) For example, Th17 could re-differentiate into a more pathogenic phenotype known as Th17(Th1-like) under the cytokine conditions IL-12, IL-23 and IL-1β (Figure1). under the cytokine conditions IL-12, IL-23 and IL-1β (Figure 1). Figure 1. NaïveNaïve CD4+ CD4+ TT cells cells differentiation. differentiation. After After migratin migratingg from from the the thymus thymus to to the the periphery, periphery, CD4+ CD4+ T cells didifferentiatefferentiate in in the the periphery periphery into into Th1, Th1, Th2, Th Th17,2, Th17, and and Treg. Treg. CD4 CD4++ T cells T cells are highlyare highly plastic plastic with withpossibility possibility of changing of changing the fate the of fate the of cell the based cell onbased its cytokines’on its cytokines’ microenvironment. microenvironment. Tregs known Tregs knownfor their for ability their toability suppress to suppress proinflammatory proinflammatory CD4+ TCD4+ cells T can cells themselves can themselves be converted be converted to highly to highlypathogenic pathogenic population population under the under action the of acti IL-1,on IL-6,of IL-1, and IL-6, IL-23. and Adapted IL-23. Adapted from [4], from copyright [4], copyright Bhaumik Bhaumikand Basu, and 2017. Basu, 2017. 2. CD4+ T Cells Infiltration Affects Alzheimer’s Disease Prognosis 2. CD4+ T Cells Infiltration Affects Alzheimer’s Disease Prognosis Our current understanding of CD4 T cells interaction with the brain during AD suggests that Our current understanding of CD4++ T cells interaction with the brain during AD suggests that allowing anti-inflammatory CD4 T cells infiltration while selectively limiting proinflammatory CD4 allowing anti-inflammatory CD4++ T cells infiltration while selectively limiting proinflammatory+ CD4+T cells T couldcells could enhance enhance the diseasethe disease prognosis. prognosis. Exploiting Exploiting CD4 CD4++ T T cells cells infiltration infiltration inin ADAD requires solving the the CD4+ CD4+ TT cells cells paradox paradox [5,6]. [5,6 It]. was It was reported reported that that these these CD4+ CD4 T cells+ T cellsdo not do proliferate not proliferate near β thenear area the areaof the of theplaques plaques [7]. [7However,]. However, CD4+ CD4 T+ cells,T cells, which which are are reactive reactive for for amyloid amyloid β,, produce proinflammatoryproinflammatory cytokines, thus co contributingntributing to AD inflammatoryinflammatory response. Data also suggest that depletion ofof hippocampal hippocampal T cellsT cells infiltration infiltration in tau-driven in tau-driven AD mouse AD mouse models models decreased decreased spatial cognitive spatial cognitiveimpairments impairments [8]. Interestingly, [8]. Interestingly, the drug bexarotene the drug [9 ]bexarotene that causes [9] apoptosis that causes in T cells apoptosis seemed in to reverseT cells β seemedthe course to ofreverse AD [10 the]. Conversely,course of AD mice [10]. lacking Conver lymphocytessely, mice showlacking a higherlymphocytes tendency show of amyloid a higher tendencyplaques growth of amyloid [11]. Theβ plaques solution growth to this [11]. paradox The couldsolution be relatedto this toparadox the variability could be of related the impact to the of variabilityvarious T cellof the subpopulations impact of various on AD T cell (Table subpopulations1). Alterations on inAD the (Table levels 1). of Alterations various subpopulations in the levels of variousof CD4+ subpopulationsT cells were identified of CD4+ inT thecells Alzheimer were iden patients’tified in the blood. Alzheimer Overall, patients’ there was blood. a rise Overall, in the therefrequency was ofa CD4rise +incells the includingfrequency FoxP3 of CD4++ and cells Th17 including subpopulations FoxP3+ [12 and]. Specific Th17 subpopulations T cell subpopulations [12]. Specificcould be T performing cell subpopulations an anti-inflammatory could be performing function byan producing anti-inflammatory neurotrophic function factors by thatproducing protect β neurotrophicneurons by stimulating factors that the protect phagocytosis neurons by activity stimul byating microglia the phagocytosis and thus helpactivity to reduce by microglia amyloid and thus help to reduce amyloid β deposition [13]. Th2 CD4+ T cells were reported to have a protective effect against AD [14] through their ability to induce the production of Aβ autoantibodies [15]. Pharmaceutics 2020, 12, 880 3 of 18 deposition [13]. Th2 CD4+ T cells were reported to have a protective effect against AD [14] through their ability to induce the production of Aβ autoantibodies [15]. Moreover, reduction of regulatory T cells numbers shortened the time before APPPS1 mice showed a reduction in their cognitive abilities. Additionally, increasing the frequency of regulatory T cells