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System Inflammation Macrophages/Microglia in Central Nervous Brain Dendritic Cells

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System Inflammation Macrophages/Microglia in Central Nervous Brain Dendritic Cells Brain Dendritic Cells and Macrophages/Microglia in Central Nervous System Inflammation This information is current as Hans-Georg Fischer and Gaby Reichmann of September 25, 2021. J Immunol 2001; 166:2717-2726; ; doi: 10.4049/jimmunol.166.4.2717 http://www.jimmunol.org/content/166/4/2717 Downloaded from References This article cites 51 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/166/4/2717.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 25, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Brain Dendritic Cells and Macrophages/Microglia in Central Nervous System Inflammation1 Hans-Georg Fischer2 and Gaby Reichmann Microglia subpopulations were studied in mouse experimental autoimmune encephalomyelitis and toxoplasmic encephalitis. CNS .inflammation was associated with the proliferation of CD11b؉ brain cells that exhibited the dendritic cell (DC) marker CD11c These cells constituted up to 30% of the total CD11b؉ brain cell population. In both diseases CD11c؉ brain cells displayed the surface phenotype of myeloid DC and resided at perivascular and intraparenchymatic inflammatory sites. By lacking prominent phagocytic organelles, CD11c؉ cells from inflamed brain proved distinct from other microglia, but strikingly resembled bone marrow-derived DC and thus were identified as DC. This brain DC population comprised cells strongly secreting IL-12p70, whereas coisolated CD11c؊ microglia/brain macrophages predominantly produced TNF-␣, GM-CSF, and NO. In comparison, the ؊ DC were more potent stimulators of naive or allogeneic T cell proliferation. Both DC and CD11c microglia/macrophages from Downloaded from inflamed brain primed naive T cells from DO11.10 TCR transgenic mice for production of Th1 cytokines IFN-␥ and IL-2. Resting microglia that had been purified from normal adult brain generated immature DC upon exposure to GM-CSF, while CD40 ligation triggered terminal maturation. Consistently, a functional maturation of brain DC was observed to occur following the onset of encephalitis. In conclusion, these findings indicate that in addition to inflammatory macrophage-like brain cells, intra- parenchymatical DC exist in autoimmune and infectious encephalitis. These DC functionally mature upon disease onset and can differentiate from resident microglia. Their emergence, maturation, and prolonged activity within the brain might contribute to http://www.jimmunol.org/ the chronicity of intracerebral Th1 responses. The Journal of Immunology, 2001, 166: 2717–2726. he CNS is susceptible to inflammatory diseases, although mic encephalitis (TE), which is induced by experimental infection the healthy organ is immunologically quiescent, presum- with the intracellular parasite Toxoplasma gondii. While TE is tran- T ably due to the blood-brain barrier and the relative lack of sient in mice that are genetically resistant to the pathogen (e.g., intraparenchymatic leukocytes and MHC class II expression. The BALB/c), susceptible mouse strains (e.g., C57BL/6) develop progres- current concept of brain immunity is based on experimental evi- sive lethal encephalitis during chronic infection (reviewed in Ref. 10). dence that activated T cells extravasate into the brain but undergo Common to EAE and TE is a type 1 CD4ϩ T cell-mediated immu- apoptosis upon contact with local APC or by other microenviron- nopathology, although it is still unclear how the intracerebral T cell by guest on September 25, 2021 mental signals (1–3). An intracerebral T cell response is likely to response is polarized. In EAE, brain microglia that function as resi- be further inhibited by the antiproliferative effect of CNS lipids dent APC are thought to skew the cellular response, as they have been and the constitutive expression of TGF-␤ (4–7). Despite such lim- shown to preferentially activate Th1 cells (11). Besides microglia, itations imposed on the immune system, vigorous inflammatory other potential APC are brain macrophages and astrocytes (reviewed responses can rapidly develop within the brain, resulting in the in Refs. 12 and 13) as, of course, are the dendritic cells (DC), which recruitment of naive bystander T cells (8). have been recently identified in the brains of BALB/c mice during Experimental autoimmune encephalomyelitis (EAE)3 is a mu- chronic latent TE (14). These brain DC seem to be related phenotyp- rine model of autoimmune disease directed against CNS Ags. Dis- ically to macrophages/microglia. ease is initiated in animals of susceptible strains by sensitization or Since myeloid DC progenitors are present in the newborn mouse the adoptive transfer of neural Ag, e.g., myelin basic protein-spe- brain (15) and mature upon challenge by T. gondii of glial cells in cific CD4ϩ T cells leading to multiple inflammatory, often demy- vitro (14), the emergence of brain DC in TE raises the question of elinating, lesions in spinal cord and brain (reviewed in Ref. 9). A whether these DC appear and expand as a direct consequence of prototypic model of infectious CNS inflammation is murine toxoplas- the presence of the pathogen or as a result of the local inflamma- tory reaction. In the present study we address the hypothesis that CNS inflammation in general is associated with an intracerebral Institute for Medical Microbiology and Virology, Heinrich Heine University, Dues- presence of functional DC. EAE as a noninfectious inflammatory seldorf, Germany CNS disease and progressive TE as a severe infectious encephalitis Received for publication August 22, 2000. Accepted for publication November were examined for the presence and location of brain DC. Isolated 27, 2000. DC were compared with coisolated microglia/brain macrophages The costs of publication of this article were defrayed in part by the payment of page with respect to their morphology, T cell stimulatory activity, and charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. cytokine secretion profiles. Furthermore, we delineate a Toxoplas- 1 This work was supported by grants from the Deutsche Forschungsgemeinschaft ma-independent differentiation pathway that leads from resting mi- (SFB194/B11 and Re-1334/2-1). croglia to functionally mature DC. 2 Address correspondence and reprint requests to Dr. Hans-Georg Fischer, Institute for Medical Microbiology and Virology, Universitaetsstrasse 1, D-40225 Duessel- Materials and Methods dorf, Germany. E-mail address: hans-georg.fi[email protected] Animals and induction of EAE and TE 3 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyeli- tis; BMNC, brain mononuclear cells; BrdU, 5-bromo-2Ј-deoxyuridine; DC, dendritic BALB/c and C57BL/6 mice were bred at the Tierversuchsanlage, Univer- cell(s); SN, supernatant; TE, toxoplasmic encephalitis; CD40L, CD40 ligand. sity of Duesseldorf, from breeding stock supplied by Biological Research Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 2718 DENDRITIC CELLS OF THE INFLAMED BRAIN Laboratories (Fuellinsdorf, Switzerland). SJL/NBom mice were obtained Flow cytometry from M&B (Ry, Denmark). Mice transgenic for TCR that recognize d ␣ ␤ Freshly prepared BMNC or cells isolated from brain cell culture were OVA323–339 peptide in the context of I-A (DO11.10 TCR / transgenic mice) on a BALB/c background (16) were provided by Dr. M. Kopf (Basel stained using the following Abs: biotinylated anti-CD11c mAb N418 (En- Institute of Immunology, Basel, Switzerland). EAE was elicited in 8-wk- dogen) or HL3 (PharMingen), FITC-labeled anti-F4/80 mAb CI:A3-1 and old female SJL mice according to the method of Miller and Karpus (17) by FITC-labeled anti-DEC-205 mAb NLDC-145 (Dianova, Hamburg, Ger- s.c. immunization with 180 ␮g of myelin basic protein 89–101 peptide many), and PE- or FITC-labeled anti-CD11b mAb M1/70.15, FITC-labeled ␣ (VHFFKNIVTPRTP; synthesized and HPLC purified by the Center for anti-CD8 mAb 53-6.7, and PE- or FITC-labeled anti-CD45 mAb 30-F11 Biological and Medical Research, University of Duesseldorf) in CFA con- (PharMingen). Species- and isotype-matched control Ab and FITC- or PE- taining 200 ␮gofMycobacterium tuberculosis H37Ra. In addition, mice conjugated streptavidin as secondary reagent were obtained from Phar- were injected i.p. with 400 ng of pertussis toxin (Alexis, Lausen, Switzer- Mingen. To block unspecific binding of primary Ab, cells were preincu- ␥ land) on days 0 and 2. About 70% of the animals showed symptoms that bated with anti-Fc II/IIIR mAb 2.4G2 (PharMingen). Double staining of corresponded to grades 0.5–2 (beginning tail paresis and additional hind surface markers was performed according to standard procedures (18). Pro- limb paresis, respectively) in EAE scoring (17). Mice were analyzed at the pidium iodide was added in the final wash to label dead cells, which were peak of disease. Control animals treated with CFA and pertussis toxin were excluded from the analyses. BrdU incorporated into cellular DNA was simultaneously analyzed. Female BALB/c or C57BL/6 mice were infected detected by using the BrdU flow kit (PharMingen). After surface staining, cells at 8–12 wk of age with the DX strain of T. gondii by i.p. injection with were fixed and permeabilized, and DNA was denatured as detailed in the kit three cysts prepared as previously described (14). Infection was serologi- protocol.
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