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Microglial Cell Activation Neurogenesis by Negative TAM Receptors Affect Adult Brain Neurogenesis by Negative Regulation of Microglial Cell Activation This information is current as Rui Ji, Shifu Tian, Helen J. Lu, Qingjun Lu, Yan Zheng, of September 24, 2021. Xiaomin Wang, Jixiang Ding, Qiutang Li and Qingxian Lu J Immunol 2013; 191:6165-6177; Prepublished online 15 November 2013; doi: 10.4049/jimmunol.1302229 http://www.jimmunol.org/content/191/12/6165 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2013/11/18/jimmunol.130222 Material 9.DC1 http://www.jimmunol.org/ References This article cites 100 articles, 32 of which you can access for free at: http://www.jimmunol.org/content/191/12/6165.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 24, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average 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 © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology TAM Receptors Affect Adult Brain Neurogenesis by Negative Regulation of Microglial Cell Activation Rui Ji,*,† Shifu Tian,* Helen J. Lu,* Qingjun Lu,‡,x,{ Yan Zheng,{ Xiaomin Wang,{ Jixiang Ding,‖ Qiutang Li,*,# and Qingxian Lu*,†,# TAM tyrosine kinases play multiple functional roles, including regulation of the target genes important in homeostatic regulation of cytokine receptors or TLR-mediated signal transduction pathways. In this study, we show that TAM receptors affect adult hip- pocampal neurogenesis and loss of TAM receptors impairs hippocampal neurogenesis, largely attributed to exaggerated inflamma- tory responses by microglia characterized by increased MAPK and NF-kB activation and elevated production of proinflammatory cytokines that are detrimental to neuron stem cell proliferation and neuronal differentiation. Injection of LPS causes even more severe inhibition of BrdU incorporation in the Tyro32/2Axl2/2Mertk2/2 triple-knockout (TKO) brains, consistent with the LPS- elicited enhanced expression of proinflammatory mediators, for example, IL-1b, IL-6, TNF-a, and inducible NO synthase, and this Downloaded from effect is antagonized by coinjection of the anti-inflammatory drug indomethacin in wild-type but not TKO brains. Conditioned medium from TKO microglia cultures inhibits neuron stem cell proliferation and neuronal differentiation. IL-6 knockout in Axl2/2 Mertk2/2 double-knockout mice overcomes the inflammatory inhibition of neurogenesis, suggesting that IL-6 is a major down- stream neurotoxic mediator under homeostatic regulation by TAM receptors in microglia. Additionally, autonomous trophic function of the TAM receptors on the proliferating neuronal progenitors may also promote progenitor differentiation into imma- ture neurons. The Journal of Immunology, 2013, 191: 6165–6177. http://www.jimmunol.org/ icroglial cells, a diverse set of innate immune cells brain injury and chronic degenerative diseases (4–9). However, distributed throughout the entire CNS, actively scan the chronic inflammation and uncontrolled activation of microglia are M CNS microenvironment (1) and provide trophic or detrimental to neuronal functions and neurogenesis (10). maintenance support for normal neuron activity (2). Serving as Microglial cells express TLRs, which can be activated by en- a major immunosurveillance cell type in the CNS (3), microglia dogenous and exogenous ligands (11–13). Activation of TLRs express all necessary receptors and molecules for recognition of causes rapid activation of microglial cells and initiates multiple invading microbes, pathogenic stimuli, proinflammatory cytokines, downstream signaling pathways, with the most common being the by guest on September 24, 2021 and cellular debris (spent or damaged neuronal organelles). When Erk1/2 and p38 MAPK pathway and the IkB kinase (IKK)/NF-kB activated, they are able to mount rapid innate immune responses signal transduction pathway, which lead, respectively, to activation with increased production of proinflammatory cytokines and che- of AP-1 or NF-kB and their subsequent nuclear binding to AP-1 mokines not only in response to systemic infection, but also to and kB binding sites on the promoters of multiple proinflam- matory genes (14–18). LPS from Gram-negative bacteria binds specifically to TLR4 on microglia and triggers intracellular sig- *Department of Ophthalmology and Visual Sciences, University of Louisville School of naling through the MAPK or IKK/NF-kB pathway, leading to rapid Medicine, Louisville, KY 40202; †Department of Anatomical Sciences and Neurobiology, transcriptional activation of innate immune-responsive genes, in- University of Louisville School of Medicine, Louisville, KY 40202; ‡Beijing Tongren Eye x cluding those coding for IL-1b,IL-6,andTNF-a. Although Institute, Beijing Capital Medical University, Beijing 100050, China; Beijing School of Ophthalmology, Beijing Capital Medical University, Beijing 100050, China; {Basic Col- microglia are vital in immune surveillance and in defending the ‖ lege of Medicine, Beijing Capital Medical University, Beijing 100050, China; Birth CNS from foreign or local danger, unrestrained and prolonged Defects Center, University of Louisville School of Dentistry, Louisville, KY 40202; and #James Graham Brown Cancer Center, University of Louisville School of Medicine, activation of brain-resident microglia is detrimental to normal Louisville, KY 40202 brain function and neuronal survival. There is evidence that sys- Received for publication August 26, 2013. Accepted for publication October 9, 2013. temic or local chronic inflammation in the CNS is detrimental not This work was supported by National Institutes of Health Grant R01 EY018830 and by only to normal neural function (19), but also to the neurogenesis the Research to Prevent Blindness special award (to Qingxian Lu). Q. Li was supported and differentiation of neuronal stem cells (NSCs) into immature by National Institutes of Health Grant R01 EY019891. Qingxian Lu and J.D. were sup- neurons (10, 20–24). LPS-elicited microglial inflammation indu- ported by an Institutional Development Award from the National Institute of General Medical Sciences of the National Institutes of Health under Grant P20GM103453. ces the release of proinflammatory cytokines affecting NSC pro- Address correspondence and reprint requests to Dr. Qingxian Lu, University of liferation in vitro and inhibiting hippocampal neurogenesis and Louisville School of Medicine, 301 E. Muhammad Ali Boulevard, Louisville, KY neuronal differentiation, and these negative effects are antagonized 40202. E-mail address: [email protected] by immunosuppressive drugs (21–28). The online version of this article contains supplemental material. Interestingly, microglia may have evolved to keep the brain Abbreviations used in this article: DC, dendritic cell; DCX, doublecortin; DG, dentate immune response in close check. To avoid exaggerated immune gyrus; DKO, double-knockout; GFAP, glial fibrillary acidic protein; IKK, IkB kinase; iNOS, inducible NO synthase; NSC, neural stem cell; poly(I:C), polyinosinic- responses to infection or pathogenic changes, innate immune cells, polycytidylic acid; qPCR, quantitative PCR; SGZ, subgranular zone; SOCS, suppres- including microglia, have developed several regulatory mecha- sor of cytokine signaling; SVZ, subventricular zone; TAM, Tyro3, Axl, and Mertk; nisms to terminate their own innate immune responses. The best TKO, triple-knockout; WT, wild-type. studied mechanisms for termination of proinflammatory cytokine Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 gene expression include 1) the rapid cytoplasmic re-expression of www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302229 6166 TAM RECEPTORS AND ADULT NEUROGENESIS IkB that inhibits NF-kB transcriptional activity, 2) the quick gain Reagents and materials of phosphatases causing dephosphorylation of MAPKs, and 3) the The NSC culture supplements B-27 (1003) and N-2 (503) were purchased efficient suppression and termination of multiple cytokine receptor from Invitrogen (San Diego, CA). Recombinant mouse Gas6 was pur- signaling by newly synthesized suppressor of cytokine signaling chased from R&D Systems (Minneapolis, MN). LPS (Escherichia coli (SOCS) protein (15) or transcriptional repressors for proinflammatory serotype 055:B5) and indomethacin were purchased from Sigma-Aldrich. cytokine genes (29). The Abs used for Western blotting were rabbit polyclonal anti-mouse p38 or anti-mouse pErk and mouse polyclonal anti–phospho-p38 and anti- In a search for upstream modulators that inhibit cytokine re- mouse Erk42/44 (all from Santa Cruz Biotechnology, Santa Cruz, CA), ceptor signaling, the Tyro3, Axl, and Mertk (TAM) receptor ty- HRP-conjugated donkey or sheep polyclonal anti-goat/rabbit/mouse IgG rosine kinases, which are expressed on dendritic cells (DCs) and (Amersham Biosciences, Piscataway, NJ), goat anti-mouse Axl,
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