DeepDyve requires Javascript to function. Please enable Javascript on your browser to continue.
Repeated immune activation with low-dose lipopolysaccharide attenuates the severity of Huntington's disease in R6/2 transgenic mice Repeated immune activation with low-dose lipopolysaccharide attenuates the severity of...
Lee, Sung Won; Park, Hyun Jung; Im, Wooseok; Kim, Manho; Hong, Seokmann
2018-07-04 00:00:00
NEUROBIOLOGY & PHYSIOLOGY ANIMAL CELLS AND SYSTEMS 2018, VOL. 22, NO. 4, 219–226 https://doi.org/10.1080/19768354.2018.1473291 Repeated immune activation with low-dose lipopolysaccharide attenuates the severity of Huntington’s disease in R6/2 transgenic mice a a b b a Sung Won Lee *, Hyun Jung Park *, Wooseok Im *, Manho Kim and Seokmann Hong Department of Integrative Bioscience and Biotechnology, Institute of Anticancer Medicine Development, Sejong University, Seoul, Korea; Department of Neurology, Seoul National University Hospital, Seoul, South Korea ABSTRACT ARTICLE HISTORY Received 20 February 2018 Huntington’s disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin Revised 4 April 2018 gene. Previously, therapeutic approaches using anti-inflammatory agents were reportedly not Accepted 8 April 2018 effective for preventing HD progression. Since whether immune responses contribute to the onset of HD is not entirely understood, we herein investigated the role of immune activation in KEYWORDS HD using the R6/2 transgenic (Tg) HD model mouse. IL12 production and the expression of Huntington’s disease; R6/2 costimulatory molecules (e.g. CD86 and CD40) on innate immune cells (DCs and macrophages) transgenic mice; were diminished in the disease stage of R6/2 Tg mice. Moreover, the number of adaptive T cells lipopolysaccharide; Dendritic + + + (CD4 and CD8 T cells) and the frequency of effector memory phenotype CD4 T cells were cells; macrophages decreased in these mice. These results suggest that the severity of HD is closely related to an impaired immune system and might be reversed by activation of the immune system. Since lipopolysaccharide (LPS), a potent TLR4 agonist, activates immune cells, we evaluated the effect of immune activation on the pathogenesis of HD using LPS. The repeated immune activation with low-dose LPS significantly recovered the impaired immune status back to normal levels and attenuated both severe weight loss and the increased clasping phenotype found in the disease stage of R6/2 Tg mice, consequently resulting in prolonged survival. Taken together, these results strongly indicate that immune activation has beneficial influences on alleviating HD pathology and could provide new therapeutic strategies for HD. 1. Introduction immunity, which refers to the first line of defense Huntington’s disease (HD) is a dominantly inherited neu- against pathogens, and (2) adaptive immunity, which rodegenerative disorder caused by a genetic defect. This refers to the antigen-specific protection against a condition results from the expansion of cytosine- specific pathogen. Dendritic cells (DCs), as innate adenine-guanine (CAG) trinucleotide repeats in exon 1 immune cells, are professional antigen-presenting cells of the gene encoding huntingtin (HTT) protein, resulting (APCs) that specialize in presenting exogenous and + + in the expression of mutant HTT (MacDonald et al. 1993). endogenous antigens to CD4 and CD8 T cells, respect- HD patients display typical clinical symptoms, such as ively. Activated/matured DCs secrete high levels of a Th1- uncontrolled movements of the limbs and trunk, cogni- polarizing cytokines, such as IL12, and express increased tive deficits and emotional disturbances (Walker 2007). levels of costimulatory molecules, including CD86 and HTT is expressed in most cells, including neurons, and CD40, leading to optimal T cell activation and survival its mutant form is also shown in the brain, adipose (Merad et al. 2013). Although the contribution of DCs tissue, muscle, and immune system (Lodi et al. 2000; to pathogenic or inhibitory effects on auto-inflammatory Phan et al. 2009; van der Burg et al. 2009). The R6/2 trans- central nervous system (CNS) disease, such as multiple genic (Tg) mouse is the most commonly used HD animal sclerosis (MS), have been well defined (Zozulya et al. model, which expresses an N-terminal fragment with 2010; Lee et al. 2015), little is known about the function more than 150 CAG repeats in HTT exon 1 (Mangiarini of DCs in neurodegenerative diseases, including HD. et al. 1996). Macrophages, another type of professional APC, are dis- The mammal possesses two types of immune systems tributed in various tissues, and particularly the CNS-resi- that work together to defend the body: (1) innate dent macrophages, called microglia, can participate in CONTACT Seokmann Hong shong@sejong.ac.kr Department of Integrative Bioscience and Biotechnology, Institute of Anticancer Medicine Development, Sejong University, Seoul 143-747, Korea *Sung Won Lee, Hyun Jung Park, and Wooseok Im contributed equally to this work. © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 220 S. W. LEEETAL. the maintenance of neuronal synapses and glutamate 2.2. Intraperitoneal injection of LPS into mice for uptake in addition to antigen presentation (London inducing immune activation et al. 2013). LPS derived from Escherichia coli (serotype 0111:B4) The pathogenesis of HD has been associated with was purchased from Sigma-Aldrich (St. Louis, MO, inflammatory responses elicited by accumulation of USA). For survival experiments, R6/2 Tg mice were mutant HTT proteins due to mitochondrial dysfunction intraperitoneally (i.p.) injected with LPS (2 μg) dis- (Bossy-Wetzel et al. 2008; Salminen et al. 2012). The solved in phosphate buffered saline (PBS) once a plasma level of pro-inflammatory cytokines, such as IL6 week starting from 5 weeks of age for 12 weeks. Litter- and IL8, were increased in HD patients compared to mate R6/2 Tg mice injected with PBS were only used as that in healthy subjects (Bjorkqvist et al. 2008). Treatment negative controls. The survival rate for both groups of of anti-inflammatory minocycline, a second-generation mice was monitored and recorded every week after tetracycline (Bastos et al. 2007), delays HD progression injection. In addition, R6/2 Tg mice injected once a in the R6/2 Tg mice (Chen et al. 2000). However, some week with either LPS (2 μg) or PBS (control) were studies have reported that minocycline cannot protect sacrificed after a total of 8 injections and subjected mice from HD (Smith et al. 2003; Mievis et al. 2007). More- to immunological analysis. over, anti-inflammatory treatment with acetylsalicylate or rofecoxib failed to protect the progression of HD (Norflus et al. 2004), suggesting that inflammatory con- 2.3. Genotyping of mice dition might be a sign rather than a direct critical To confirm the presence of HTT mutant transgene, factor causing the disease. genomic DNA from tail biopsies was used to amplify a Here, we demonstrated that R6/2 Tg mice with the 170 bp fragment that was only detectable in mice carry- onset of HD show a noticeably attenuated immune ing the HD transgene. The following primers were used status whereas mice with pre-manifest HD display for PCR genotyping: forward 5 -CCG CTC AGG TTC TGC an immune status comparable to that of wild-type ′ ′ TTT TA-3 ; and reverse 5 -TGG AAG GAC TTG AGG GAC (WT) littermate control mice, regarding both innate TC-3 . and adaptive immune responses. Moreover, the treat- ment of HD-onset R6/2 Tg mice with low-dose lipopo- lysaccharide (LPS) stimulated innate immune cells, 2.4. Mouse brain isolation and clasping test including DCs, leading to activation of T cells, ulti- The mice were anesthetized by using ketamine and xyla- mately delaying disease progression. Therefore, our zine (40 and 4 mg/kg, respectively) and were perfused results provide evidence supporting the preventive through the left cardiac ventricle with cold PBS (pH = effects of low levels of inflammation on HD 7.4) for 3 min to remove cells from the blood vessels. pathogenesis. The brain was removed. For testing clasping, 4- or 12- week-old mice were suspended by the tail for 30 s, and 2. Materials and methods the foot-clasping time was scored as follows: 3, >10 s; 2, 5–10 s; 1, 0–5 s; 0, 0 s (Nguyen et al. 2005). 2.1. Mice HD Tg mice of the R6/2 line (B6CBA-Tg(HDex- 2.5. Cell isolation and culture on1)62Gpb/3J; hereafter R6/2 Tg mice) were purchased from the Jackson Laboratory. All mice in the present A single-cell suspension of splenocytes was prepared study were maintained at Sejong University and used and resuspended in RPMI complete medium consisting for experiments at 6–12 weeks of age. The mice were of RPMI 1640 (Gibco BRL, USA) medium supplemented maintained on a 12-hour light/12-hour dark cycle in a with 10% FBS, 10 mM HEPES, 2 mM L-glutamine, 100 temperature-controlled barrier facility with free access units/mL penicillin-streptomycin, and 5 mM 2- to food and water. The mice were fed a γ-irradiated mercaptoethanol. sterile diet and provided autoclaved tap water. Age- and sex-matched R6/2 Tg and WT littermate control 2.6. Flow cytometry mice were used for all experiments. The animal exper- iments were approved by the Institutional Animal The following monoclonal antibodies (mAbs) from BD Care and Use Committee at Sejong University (SJ- Biosciences were used: fluorescein isothiocyanate 20160704). The present experiments were conducted (FITC)-, phycoerythrin (PE)-Cy7-, or allophycocyanin in a blinded and randomized trial. (APC)-conjugated anti-CD3ε (clone 145-2C11); FITC- or ANIMAL CELLS AND SYSTEMS 221 PE-Cy7-conjugated anti-CD4 (clone RM4-5); FITC- or APC- pathological properties of the disease (Mangiarini et al. conjugated anti-CD11c (clone HL3); PE-Cy7-conjugated 1996). To confirm the characteristics during natural anti-CD11b (clone M1/70); PE-conjugated anti-CD62L disease progression in R6/2 Tg mice, we compared the (clone MEL-14); PE-Cy7-conjugated anti-CD8 (clone disease phenotypes of R6/2 Tg mice with those of the 53-6.7); biotin-conjugated anti-CD86 (clone GL1); PE-con- WT littermate control mice at either 4 or 12 weeks of jugated anti-IL12p40 (clone C15.6); and FITC- or PE-con- age. The brains of 12-week-old but not 4-week-old R6/ jugated anti-IgG1 (isotype control) (clone R3-34). The 2 Tg mice weighed approximately 25% less than those following mAbs from eBioscience (San Diego, CA, USA) from WT littermates of the same age (Figure 1B), indicat- were used: APC-conjugated anti-F4/80 (clone BM8); PE- ing that 12-week-old R6/2 Tg mice showed a more pro- conjugated anti-CD40 (clone 3/23). To perform surface gressed disease phenotype. Next, we compared the staining, cells were harvested and washed twice with clasping behavior and body weight between R6/2 Tg cold 0.5% BSA-containing PBS (FACS buffer). To block mice and WT littermates at either 4 or 12 weeks of age. Fc receptors, the cells were incubated with anti-CD16/ Twelve-week-old but not 4-week-old R6/2 Tg mice exhib- CD32 mAbs on ice for 10 min and subsequently ited a substantial increase of clasping phenotype (Figure stained with fluorescence-labeled mAbs. Flow cytometric 1C) and displayed decreased body weight compared data were acquired using a FACSCalibur flow cytometer with WT littermates of the same age (Figure 1D). (Becton Dickson, San Jose, CA, USA) and analyzed Since changes in immune responses have been corre- using FlowJo software (Tree Star Inc., Ashland, OR, USA). lated with the severity of HD (Soulet & Cicchetti 2011), we compared the spleen weight as well as the total number of splenocytes during HD development in R6/2 Tg mice. 2.7. Intracellular cytokine staining Unlike 4-week-old R6/2 Tg mice, both the spleen weight and the total number of splenocytes were significantly For intracellular staining, splenocytes were incubated decreased in 12-week-old R6/2 Tg mice compared to with brefeldin A, an intracellular protein transport inhibi- those of their WT littermates (Figure 1E). These data indi- tor (10 μg/ml), in RPMI medium for 2 h at 37°C. The cells cated that the progression of HD into late-stage is were stained for cell surface markers, fixed with 1% par- strongly associated with reduced immune activation. aformaldehyde, washed once with cold FACS buffer, and permeabilized with 0.5% saponin. The permeabilized cells were then stained for an additional 30 min at 3.2. HD-onset R6/2 Tg mice exhibit impaired room temperature with the indicated mAbs (PE-conju- functions of APCs, consistent with reduced levels gated anti-IL12, or PE-conjugated isotype control rat of T cell immune responses IgG mAbs). More than 5000 cells per sample were As DCs and macrophages are involved in the regulation acquired using a FACSCalibur, and the data were ana- of CNS function other than the induction of T cell polar- lyzed using the FlowJo software package (Tree Star, ization (Zozulya et al. 2010; London et al. 2013; Merad Ashland, OR, USA). et al. 2013), we next examined whether the progressed HD phenotype is closely related with alteration of APC 2.8. Statistical analysis number and function. The frequency and absolute number of these cells were significantly reduced in 12- Statistical significance was determined using Excel week-old but not 4-week-old R6/2 Tg mice (Figure 2A (Microsoft, USA). Student’s t-test was performed for the and B). Next, to determine whether there is any attenu- comparison of two groups. *P < 0.05, **P < 0.01, and ation of DC activation, we measured the expression ***P < 0.001 were considered to be significant in the Stu- level of activation markers, including CD86, CD40, and dent’s t-test. Two-way ANOVA analysis was carried out IL12, in R6/2 Tg mice. Unlike no difference in the using the VassarStats (http://faculty.vassar.edu/lowry/ # ## ### expression of costimulatory molecules, CD86 and CD40, VassarStats.html). P < 0.05, P < 0.01, and P < 0.001 between R6/2 Tg mice and WT littermates at pre- were considered to be significant in the two-way ANOVA. manifest stage HD (4-week-old), the expression levels of these molecules were significantly decreased in R6/2 3. Results Tg mice at late stage HD (12-week-old) compared to that in WT littermates (Figure 2C). Additionally, IL12 3.1. Dramatic reduction in splenic immune cells at production was diminished in R6/2 Tg mice at 12 the disease stage of R6/2 Tg mice weeks of age, suggesting that attenuated immune The R6/2 Tg mouse is a well-characterized animal model responses are correlated with the progression of HD for HD, which represents behavioral, neuronal, and (Figure 2D). Our results strongly indicated that both 222 S. W. LEEETAL. Figure 1. HD-onset R6/2 Tg mice show reduced levels of splenocytes. (A) Genotyping HD mutant gene by PCR analysis. HTT mutant PCR band sizes 170 bp long. M: marker; Lane 1: positive control; Lane 2: negative control; Lane 3: HD positive; Lane 4: HD negative. (B) Brains were harvested from WT littermates or R6/2 Tg mice of 4 or 12 weeks of age (left panel) and their brain weights were evaluated (right panel). (C) Clasping test and (D) body weight were evaluated from WT littermates and R6/2 Tg mice of 4 or 12 weeks of age. (E) Spleens were prepared from WT littermates or R6/2 Tg mice of 4 or 12 weeks of age and the spleen weight and splenocyte number were eval- uated. The mean values ± SD (n = 4 in B, C, D, and E; per group in the experiment; Student’s t-test; **P < 0.01, ***P < 0.001) are shown. # ## ### Two-way ANOVA (genotype × time) showed an interaction between these two factors ( P < 0.05, P < 0.01, and P < 0.001). quantitative and qualitative reductions of APCs in HD- 3.3. Low-dose LPS treatment can delay HD onset R6/2 Tg mice were dependent on the stage of progression in R6/2 Tg mice disease progression. LPS, which is one of the most potent TLR4 agonists, trig- Since adaptive immune responses do not occur gers the activation of innate immune cells (most notably without innate immune responses, we further investi- DCs and macrophages) (Mogensen 2009). Thus, to assess gated whether adaptive immune cells, such as CD4 the effect of LPS on the course of HD, R6/2 Tg mice were and CD8 T cells, could be altered by HD progression. treated with low-dose LPS and were subsequently mon- In 12-week-old but not 4-week-old R6/2 Tg mice, the itored for phenotypes, including survival, clasping score, number of these cells was significantly decreased com- and body weight. We found that the survival duration paredwiththatinWTlittermates (Figure 2E). Next, to was significantly prolonged in LPS-treated R6/2 Tg investigate the functionality (activation status) of T mice compared to that in the untreated WT littermate cells, we compared the CD62L surface expression (a control group (Figure 3A). Body weight was also assessed marker for effector/memory cells) between R6/2 Tg in R6/2 Tg mice treated with either LPS or vehicle for 9 and WT littermate control mice. The frequency of weeks starting at 5 weeks of age. The weight loss was low + CD62L effector/memory CD4 T cells was diminished much less severe in R6/2 Tg mice treated with LPS in HD-onset R6/2 Tg mice (Figure 2F). Thus, we provide compared to that in the WT littermate control mice the evidence that the reduced frequency of effector T (Figure 3B). Furthermore, the clinical score of clasping cells is correlated with APC defects affected by HD phenotype was attenuated in LPS-treated R6/2 Tg mice progression. ANIMAL CELLS AND SYSTEMS 223 Figure 2. HD-onset R6/2 Tg mice exhibit impaired functions of APCs, concordant with reduced levels of T cell immune responses. (A-D) Splenocytes were isolated from the spleens of WT littermates and R6/2 Tg mice at either 4 or 12 weeks of age. (A) The percentage of + + - CD11b F4/80 macrophages among CD11c splenic populations was evaluated via flow cytometry (left panels). The absolute cell number of macrophages was determined (right panels). (B) The percentage of CD11c splenic population was evaluated via flow cyto- metry (left panels). The absolute cell number of DCs was determined (right panels). (C) Surface expressions of CD86 and CD40 and (D) + + - + intracellular IL12 production were analyzed in macrophages (CD11b F4/80 CD11c ) and DCs (CD11c ). Top, representative FACS plot; bottom, summary figures. The mean values ± SD (n = 4 in A, B, C, and D; per group in the experiment; Student’s t-test; *P < 0.05, **P < # ## 0.01, ***P < 0.001) are shown. Two-way ANOVA (genotype × time) showed an interaction between these two factors ( P < 0.05, P < ### 0.01, and P < 0.001). (E-F) Splenocytes were isolated from the spleens of WT littermates and R6/2 Tg mice at either 4 or 12 weeks of + + + + + - age. (E) The frequencies of total T cells, CD4 T cells, and CD8 T cells were calculated by gating on CD3 , CD3 CD4 CD8 , and + - + + CD3 CD4 CD8 populations, as observed in the upper left panels. (F) The frequencies of effector/memory CD4 T cells and naive + + + low + + high CD4 T cells were calculated by gating on CD3 CD4 CD62L and CD3 CD4 CD62L populations, as observed in the left panels. The mean values ± SD (n = 4 in E and F; per group in the experiment; Student’s t-test; **P < 0.01, ***P < 0.001) are shown. Two- ## ### way ANOVA (genotype × time) showed an interaction between these two factors ( P < 0.01, and P < 0.001). 224 S. W. LEEETAL. Figure 3. Low-dose LPS treatment prevents HD progression in R6/2 Tg mice. (A) R6/2 Tg mice were i.p. injected with either PBS (n =8) or low-dose LPS (2 μg) (n = 8) once per week starting from 5 weeks of age for total 12 weeks. The survival rate of these mice was monitored every week after LPS treatment. (B-E) R6/2 Tg mice were i.p. injected with either PBS (n = 4) or low-dose LPS (2 μg) (n = 4) treatment from 5 to 14 weeks old. (B) The mice were also weighed weekly from 5 to 14 weeks old. (C) Mice were tested for hind limb clasping behavior at 7 weeks after LPS injection. (D) The absolute cell number of total splenocytes, macrophages, and DCs were determined at 9 weeks after LPS injection. (E) Surface expressions of CD86 and CD40 and intracellular IL12 production + + - + were analyzed in macrophages (CD11b F4/80 CD11c ) and DCs (CD11c ) at 9 weeks after LPS injection. The mean values ± SD (n = 8 in A; n = 4 in B, C, D, and E; per group in the experiment; Student’s t-test; *P < 0.05, **P < 0.01, ***P < 0.001) are shown. compared with that in the PBS-treated WT littermate 4. Discussion control group (Figure 3C). Although previous studies have suggested that pro- Next, we examined whether LPS treatment has any inflammatory conditions by immune cells cause an accel- influence on the alteration of innate immune cells in eration of HD, the efficacy of anti-inflammatory agents in R6/2 Tg mice. The number of splenic macrophages and treating HD has not been satisfied (Norflus et al. 2004). The DCs, as well as total splenocytes, was significantly role of immune activation in HD has not been fully eluci- increased in LPS-treated R6/2 Tg mice compared with dated. Therefore, we aimed to determine whether those in the PBS-treated WT littermate control group immune activation modulates the pathogenesis of HD. (Figure 3D). Moreover, the expression of costimulatory In the late HD stage of R6/2 Tg mice, the cell number molecules (CD86 and CD40) and IL12 production were and activation status of adaptive immune cells, as well both up-regulated in LPS-treated R6/2 Tg mice com- as innate immune cells (DCs and macrophages), were pared to that in the PBS-treated WT littermate control diminished, suggesting that the severity of HD might be group (Figure 3E). Taken together, these results demon- associated with an impaired immune system. Moreover, strated that LPS treatment could prevent the pathogen- we showed that immune activation through repeated esis of HD through the activation of innate immune LPS treatment significantly delayed the progression of HD. responses. ANIMAL CELLS AND SYSTEMS 225 Since glutamate uptake was reduced in the prefrontal In conclusion, our study provides in vivo evidence that cortex of HD patients, it has been proposed that gluta- the repeated low-dose LPS treatment could awake the mate uptake might be inversely correlated with CAG inhibited (or anergized) peripheral immune system, repeat expansion (Hassel et al. 2008). An increase of glu- which delays or prevents the further progression of HD. tamate uptake induced by up-regulation of the gluta- These findings will help to design a new therapeutic mate transporter 1 (GLT-1) attenuates HD signs in R6/2 strategy to modulate HD pathology. Tg mice (Miller et al. 2008). Based on a previous study, showing that LPS treatment increases GLT-1 expression Disclosure statement and glutamate uptake in microglia in a TNFα-dependent manner (Persson et al. 2005), the finding that LPS treat- No potential conflict of interest was reported by the authors. ment improves the clinical symptoms of HD could be associated with a change in glutamate uptake. Since Funding IFNγ signaling to astrocytes with glutamate clearance is critical for neuroprotection (Hindinger et al. 2012), it is This work was supported by Sejong University Faculty Research reasonable to speculate that IFNγ derived from LPS-acti- Fund (Grant No. 20160177). vated immune cells might induce paracrine cytokine stimulation of astrocytes, thereby attenuating the pro- References gression of HD. Thus, it will be of interest to investigate this issue in the future. Bastos LF, Merlo LA, Rocha LT, Coelho MM. 2007. N171-82Q HD mice were recently reported to have Characterization of the antinociceptive and anti-inflamma- tory activities of doxycycline and minocycline in different fewer IFNγ-producing CD8 T cells in response to Toxo- experimental models. Eur J Pharmacol. 576:171–179. plasma gondii infection, leading to premature death, Bjorkqvist M, Wild EJ, Thiele J, Silvestroni A, Andre R, Lahiri N, suggesting that the immune system in HD mice is down- Raibon E, Lee RV, Benn CL, Soulet D, et al. 2008. A novel regulated (Donley et al. 2016). Consistently, the present pathogenic pathway of immune activation detectable results showed that the late-symptomatic R6/2 Tg mice before clinical onset in Huntington’s disease. J Exp Med. 205:1869–1877. displayed significantly reduced levels of inflammatory Bossy-Wetzel E, Petrilli A, Knott AB. 2008. Mutant huntingtin responses. Additionally, the majority of HD patients and mitochondrial dysfunction. Trends Neurosci. 31:609– failed to control pneumonia infection, which becomes, in fact, the most common cause of death (Heemskerk Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, & Roos 2012). Thus, the adjuvant effects of LPS on the Farrell LA, Hersch SM, et al. 2000. Minocycline inhibits immune system could be useful to delay or prevent pro- caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat gression to advanced HD stage in patients. Med. 6:797–801. Although mutant HTT is expressed in the brain, which Donley DW, Olson AR, Raisbeck MF, Fox JH, Gigley JP. 2016. is the primary pathological tissue of HD, mutant HTT is Huntingtons disease mice infected with toxoplasma gondii expressed in other tissues (e.g. fat and muscle) and demonstrate early kynurenine pathway activation, altered immune system (Phan et al. 2009; van der Burg et al. CD8+ T-cell responses, and premature mortality. PLoS One. 11:e0162404. 2009; Soulet & Cicchetti 2011). It has previously been Hassel B, Tessler S, Faull RL, Emson PC. 2008. Glutamate uptake reported that mutant HTT was expressed in immune is reduced in prefrontal cortex in Huntington’s disease. cells and their migratory functions were consequently Neurochem Res. 33:232–237. impaired in peripheral myeloid cells, such as monocytes, Heemskerk AW, Roos RA. 2012. Aspiration pneumonia and as well as microglia from pre-manifest human HD death in Huntington’s disease. PLoS Curr. 4:RRN1293. patients, suggesting that immune dysfunction may be Hindinger C, Bergmann CC, Hinton DR, Phares TW, Parra GI, Hussain S, Savarin C, Atkinson RD, Stohlman SA. 2012. IFN- attributed to poly-glutamine expansion (Kwan et al. gamma signaling to astrocytes protects from autoimmune 2012). Moreover, a recent study provided clear evidence mediated neurological disability. PLoS One. 7:e42088. that the immune system can restrain the pathogenesis of Kwan W, Trager U, Davalos D, Chou A, Bouchard J, Andre R, Alzheimer’s disease, another type of neurodegenerative Miller A, Weiss A, Giorgini F, Cheah C, et al. 2012. Mutant hun- disease, via the modulation of microglial function tingtin impairs immune cell migration in Huntington disease. J Clin Invest. 122:4737–4747. (Marsh et al. 2016). Our results suggest that downregu- Lee SW, Park HJ, Jeon SH, Lee C, Seong RH, Park SH, Hong S. lated immune functions are closely correlated with the 2015. Ubiquitous over-expression of chromatin re- full-blown disease status of HD and indicate that the modeling factor SRG3 ameliorates the T cell-mediated adoptive transfer of functional immune cells (with exacerbation of EAE by modulating the phenotypes of normal HTT gene) into HD patients might be beneficial both dendritic cells and macrophages. PLoS One. 10: by retarding disease progression. e0132329. 226 S. W. LEEETAL. Lodi R, Schapira AH, Manners D, Styles P, Wood NW, Taylor DJ, Mogensen TH. 2009. Pathogen recognition and inflammatory Warner TT. 2000. Abnormal in vivo skeletal muscle energy signaling in innate immune defenses. Clin Microbiol Rev. metabolism in Huntington’s disease and dentatorubropalli- 22:240–273. Table of Contents. doluysian atrophy. Ann Neurol. 48:72–76. Nguyen T, Hamby A, Massa SM. 2005. Clioquinol down-regu- London A, Cohen M, Schwartz M. 2013. Microglia and mono- lates mutant huntingtin expression in vitro and mitigates cyte-derived macrophages: Functionally distinct populations pathology in a Huntington’s disease mouse model. Proc that act in concert in CNS plasticity and repair. Front Cell Natl Acad Sci U S A. 102:11840–11845. Neurosci. 7:34. Norflus F, Nanje A, Gutekunst CA, Shi G, Cohen J, Bejarano M, MacDonald ME, Ambrose CM, Duyao MP, Myers RH, Lin C, Fox J, Ferrante RJ, Hersch SM. 2004. Anti-inflammatory treat- Srinidhi L, Barnes G, Taylor SA, James M, Groot N, et al. ment with acetylsalicylate or rofecoxib is not neuroprotec- 1993. A novel gene containing a trinucleotide repeat that tive in Huntington’s disease transgenic mice. Neurobiol Dis. is expanded and unstable on Huntington’s disease chromo- 17:319–325. somes. Cell. 72:971–983. Persson M, Brantefjord M, Hansson E, Ronnback L. 2005. Mangiarini L, Sathasivam K, Seller M,CozensB,HarperA, Lipopolysaccharide increases microglial GLT-1 expression Hetherington C, Lawton M, Trottier Y, Lehrach H, and glutamate uptake capacity in vitro by a mechanism Davies SW, et al. 1996.Exon1of theHDgenewithan dependent on TNF-alpha. Glia. 51:111–120. expanded CAG repeat is sufficient to cause a progressive Phan J, Hickey MA, Zhang P, Chesselet MF, Reue K. 2009. neurological phenotype in transgenic mice. Cell. 87:493– Adipose tissue dysfunction tracks disease progression in 506. two Huntington’s disease mouse models. Hum Mol Genet. Marsh SE, Abud EM, Lakatos A, Karimzadeh A, Yeung ST, 18:1006–1016. Davtyan H, Fote GM, Lau L, Weinger JG, Lane TE, et al. Salminen A, Ojala J, Kaarniranta K, Kauppinen A. 2012. 2016. The adaptive immune system restrains Alzheimer’s Mitochondrial dysfunction and oxidative stress activate disease pathogenesis by modulating microglial function. inflammasomes: impact on the aging process and age- Proc Natl Acad Sci U S A. 113:E1316–E1325. related diseases. Cell Mol Life Sci. 69:2999–3013. Merad M, Sathe P, Helft J, Miller J, Mortha A. 2013. The dendritic Smith DL, Woodman B, Mahal A, Sathasivam K, Ghazi-Noori S, cell lineage: ontogeny and function of dendritic cells and Lowden PA, Bates GP, Hockly E. 2003. Minocycline and dox- their subsets in the steady state and the inflamed setting. ycycline are not beneficial in a model of Huntington’s Annu Rev Immunol. 31:563–604. disease. Ann Neurol. 54:186–196. Mievis S, Levivier M, Communi D, Vassart G, Brotchi J, Ledent C, Soulet D, Cicchetti F. 2011. The role of immunity in Huntington’s Blum D. 2007. Lack of minocycline efficiency in genetic disease. Mol Psychiatry. 16:889–902. models of Huntington’s disease. Neuromolecular Med. van der Burg JM, Bjorkqvist M, Brundin P. 2009. Beyond the 9:47–54. brain: widespread pathology in Huntington’s disease. Miller BR, Dorner JL, Shou M, Sari Y, Barton SJ, Sengelaub DR, Lancet Neurol. 8:765–774. Kennedy RT, Rebec GV. 2008. Up-regulation of GLT1 Walker FO. 2007. Huntington’s disease. Lancet. 369:218–228. expression increases glutamate uptake and attenuates the Zozulya AL, Clarkson BD, Ortler S, Fabry Z, Wiendl H. 2010. The Huntington’s disease phenotype in the R6/2 mouse. role of dendritic cells in CNS autoimmunity. J Mol Med (Berl). Neuroscience. 153:329–337. 88:535–544.
http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png
Animal Cells and Systems
Taylor & Francis
http://www.deepdyve.com/lp/taylor-francis/repeated-immune-activation-with-low-dose-lipopolysaccharide-attenuates-HxzMHm1Ny6
