Abstract
Adult hippocampal neurogenesis plays an important role in health and disease. Regulating neurogenesis may be a key mechanism in the pathophysiology and treatment of several neurobehavioral disorders such as schizophrenia, depression, autism spectrum disorders and Alzheimer’s disease. Cytokines are known to affect adult neurogenesis, but conflicting studies have been reported with regard to their actual role. Interleukine-17 (IL-17), a potent pro-inflammatory cytokine, has been shown to inhibit proliferation of neuroprogenitors and thus reduce hippocampal neurogenesis, while other studies suggested it can promote neurite outgrowth. In the present study we sought to explore the possible effect of a single dose administration of IL-17 on neurogenesis related behavior, i.e. spatial learning. Surprisingly, ICR mice injected with IL-17 (8 μg) had a significant slight improvement in spatial learning in the Morris water maze paradigm, without any changes in general locomotion compared with control mice. Indeed, the expression of neurogenesis related genes was down regulated following IL-17 treatment. However, we detected an upregulation in the expression of FGF-13, a gene promoting microtubule polymerization and neurite outgrowth, thus supporting neuronal maturation. We thus suggest that IL-17 has a complex role in regulating adult neurogenesis: inhibiting neuroprogenitors proliferation on one hand, while promoting maturation of already formed neuroblasts on the other hand. Our findings suggest that these roles can potentially affect neurogenesis related behavior. Its actual role in health and disease is yet to be determined.
Similar content being viewed by others
References
Abookasis D, Lerman D, Roth H, Tfilin M, Turgeman G (2018) Optically derived metabolic and hemodynamic parameters predict hippocampal neurogenesis in the BTBR mouse model of autism. J Biophotonics 11(3)
Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124(3):319–335
Asada M, Mizutani S, Takagi M, Suzuki H (2016) Antipsychotics promote neural differentiation of human iPS cell-derived neural stem cells. Biochem Biophys Res Commun 480(4):615–621
Benninghoff J, Grunze H, Schindler C, Genius J, Schloesser RJ, van der Ven A, Dehning S, Wiltfang J, Moller HJ, Rujescu D (2013) Ziprasidone--not haloperidol--induces more de-novo neurogenesis of adult neural stem cells derived from murine hippocampus. Pharmacopsychiatry 46(1):10–15
Beurel E, Harrington LE, Jope RS (2013) Inflammatory T helper 17 cells promote depression-like behavior in mice. Biol Psychiatry 73(7):622–630
Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V, Rosoklija GB, Stankov A, Arango V, Dwork AJ, Hen R, Mann JJ (2018) Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 22(4):589–599 e585
Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, Martino G, Schwartz M (2006) Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci 31(1):149–160
Chisholm SP, Cervi AL, Nagpal S, Lomax AE (2012) Interleukin-17A increases neurite outgrowth from adult postganglionic sympathetic neurons. J Neurosci 32(4):1146–1155
Cho ML, Kang JW, Moon YM, Nam HJ, Jhun JY, Heo SB, Jin HT, Min SY, Ju JH, Park KS, Cho YG, Yoon CH, Park SH, Sung YC, Kim HY (2006) STAT3 and NF-kappaB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice. J Immunol 176(9):5652–5661
Dommasch ED, Li T, Okereke OI, Li Y, Qureshi AA, Cho E (2015) Risk of depression in women with psoriasis: a cohort study. Br J Dermatol 173(4):975–980
Dowlatshahi EA, Wakkee M, Arends LR, Nijsten T (2014) The prevalence and odds of depressive symptoms and clinical depression in psoriasis patients: a systematic review and meta-analysis. J Investig Dermatol 134(6):1542–1551
Faigle R, Song H (2013) Signaling mechanisms regulating adult neural stem cells and neurogenesis. Biochim Biophys Acta 1830(2):2435–2448
Felger JC, Lotrich FE (2013) Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience 246:199–229
Fitzsimons CP, van Bodegraven E, Schouten M, Lardenoije R, Kompotis K, Kenis G, van den Hurk M, Boks MP, Biojone C, Joca S, Steinbusch HW, Lunnon K, Mastroeni DF, Mill J, Lucassen PJ, Coleman PD, van den Hove DL, Rutten BP (2014) Epigenetic regulation of adult neural stem cells: implications for Alzheimer’s disease. Mol Neurodegener 9:25
Fuster-Matanzo A, Llorens-Martin M, Hernandez F, Avila J (2013) Role of neuroinflammation in adult neurogenesis and Alzheimer disease: therapeutic approaches. Mediat Inflamm 2013:260925
Gage FH (2000) Mammalian neural stem cells. Science 287(5457):1433–1438
Ghosal K, Stathopoulos A, Pimplikar SW (2010) APP intracellular domain impairs adult neurogenesis in transgenic mice by inducing neuroinflammation. PLoS One 5(7):e11866
Giachino C, Barz M, Tchorz JS, Tome M, Gassmann M, Bischofberger J, Bettler B, Taylor V (2014) GABA suppresses neurogenesis in the adult hippocampus through GABAB receptors. Development 141(1):83–90
Gobshtis N, Tfilin M, Wolfson M, Fraifeld VA, Turgeman G (2017) Transplantation of mesenchymal stem cells reverses behavioural deficits and impaired neurogenesis caused by prenatal exposure to valproic acid. Oncotarget 8(11):17443–17452
Habash T, Saleh A, Roy Chowdhury SK, Smith DR, Fernyhough P (2015) The proinflammatory cytokine, interleukin-17A, augments mitochondrial function and neurite outgrowth of cultured adult sensory neurons derived from normal and diabetic rats. Exp Neurol 273:177–189
Hatakeyama J, Bessho Y, Katoh K, Ookawara S, Fujioka M, Guillemot F, Kageyama R (2004) Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development 131(22):5539–5550
Himmerich H, Schonherr J, Fulda S, Sheldrick AJ, Bauer K, Sack U (2011) Impact of antipsychotics on cytokine production in-vitro. J Psychiatr Res 45(10):1358–1365
Inestrosa NC, Varela-Nallar L (2015) Wnt signalling in neuronal differentiation and development. Cell Tissue Res 359(1):215–223
Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA (2004) Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci U S A 101(1):343–347
Kabos P, Kabosova A, Neuman T (2002) Blocking HES1 expression initiates GABAergic differentiation and induces the expression of p21(CIP1/WAF1) in human neural stem cells. J Biol Chem 277(11):8763–8766
Kempermann G, Wiskott L, Gage FH (2004) Functional significance of adult neurogenesis. Curr Opin Neurobiol 14(2):186–191
Keohane A, Ryan S, Maloney E, Sullivan AM, Nolan YM (2010) Tumour necrosis factor-alpha impairs neuronal differentiation but not proliferation of hippocampal neural precursor cells: role of Hes1. Mol Cell Neurosci 43(1):127–135
Koo JW, Russo SJ, Ferguson D, Nestler EJ, Duman RS (2010) Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc Natl Acad Sci U S A 107(6):2669–2674
Li GZ, Zhong D, Yang LM, Sun B, Zhong ZH, Yin YH, Cheng J, Yan BB, Li HL (2005) Expression of interleukin-17 in ischemic brain tissue. Scand J Immunol 62(5):481–486
Li Z, Li K, Zhu L, Kan Q, Yan Y, Kumar P, Xu H, Rostami A, Zhang GX (2013) Inhibitory effect of IL-17 on neural stem cell proliferation and neural cell differentiation. BMC Immunol 14:20
Lichtenwalner RJ, Forbes ME, Bennett SA, Lynch CD, Sonntag WE, Riddle DR (2001) Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience 107(4):603–613
Lie DC, Colamarino SA, Song HJ, Desire L, Mira H, Consiglio A, Lein ES, Jessberger S, Lansford H, Dearie AR, Gage FH (2005) Wnt signalling regulates adult hippocampal neurogenesis. Nature 437(7063):1370–1375
Liu J, Solway K, Messing RO, Sharp FR (1998) Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci 18(19):7768–7778
Liu Q, Xin W, He P, Turner D, Yin J, Gan Y, Shi FD, Wu J (2014) Interleukin-17 inhibits adult hippocampal neurogenesis. Sci Rep 4:7554
Malakouti M, Brown GE, Wang E, Koo J, Levin EC (2015) The role of IL-17 in psoriasis. J Dermatol Treat 26(1):41–44
Mathieu P, Piantanida AP, Pitossi F (2010) Chronic expression of transforming growth factor-beta enhances adult neurogenesis. Neuroimmunomodulation 17(3):200–201
Matusevicius D, Kivisakk P, He B, Kostulas N, Ozenci V, Fredrikson S, Link H (1999) Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler 5(2):101–104
Mira H, Andreu Z, Suh H, Lie DC, Jessberger S, Consiglio A, San Emeterio J, Hortiguela R, Marques-Torrejon MA, Nakashima K, Colak D, Gotz M, Farinas I, Gage FH (2010) Signaling through BMPR-IA regulates quiescence and long-term activity of neural stem cells in the adult hippocampus. Cell Stem Cell 7(1):78–89
Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302(5651):1760–1765
Perez-Asensio FJ, Perpina U, Planas AM, Pozas E (2013) Interleukin-10 regulates progenitor differentiation and modulates neurogenesis in adult brain. J Cell Sci 126(Pt 18):4208–4219
Rubio-Perez JM, Morillas-Ruiz JM (2012) A review: inflammatory process in Alzheimer’s disease, role of cytokines. ScientificWorldJournal 2012:756357
Sahay A, Hen R (2007) Adult hippocampal neurogenesis in depression. Nat Neurosci 10(9):1110–1115
Scharfman H, Goodman J, Macleod A, Phani S, Antonelli C, Croll S (2005) Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol 192(2):348–356
Schreiber R, Newman-Tancredi A (2014) Improving cognition in schizophrenia with antipsychotics that elicit neurogenesis through 5-HT(1A) receptor activation. Neurobiol Learn Mem 110:72–80
Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, Iwaki T, Okada Y, Iida M, Cua DJ, Iwakura Y, Yoshimura A (2009) Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med 15(8):946–950
Solecki DJ, Liu XL, Tomoda T, Fang Y, Hatten ME (2001) Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation. Neuron 31(4):557–568
Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, Fugger L (2008) Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 172(1):146–155
Vallieres L, Campbell IL, Gage FH, Sawchenko PE (2002) Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 22(2):486–492
Wong H, Hoeffer C (2018) Maternal IL-17A in autism. Exp Neurol 299(Pt A):228–240
Wu QF, Yang L, Li S, Wang Q, Yuan XB, Gao X, Bao L, Zhang X (2012) Fibroblast growth factor 13 is a microtubule-stabilizing protein regulating neuronal polarization and migration. Cell 149(7):1549–1564
Yang J, Jiang Z, Fitzgerald DC, Ma C, Yu S, Li H, Zhao Z, Li Y, Ciric B, Curtis M, Rostami A, Zhang GX (2009) Adult neural stem cells expressing IL-10 confer potent immunomodulation and remyelination in experimental autoimmune encephalitis. J Clin Invest 119(12):3678–3691
Yilmaz SB, Cicek N, Coskun M, Yegin O, Alpsoy E (2012) Serum and tissue levels of IL-17 in different clinical subtypes of psoriasis. Arch Dermatol Res 304(6):465–469
Zhang Z, Yan R, Zhang Q, Li J, Kang X, Wang H, Huan L, Zhang L, Li F, Yang S, Zhang J, Ren X, Yang X (2014) Hes1, a notch signaling downstream target, regulates adult hippocampal neurogenesis following traumatic brain injury. Brain Res 1583:65–78
Zhou J, Nagarkatti P, Zhong Y, Ginsberg JP, Singh NP, Zhang J, Nagarkatti M (2014) Dysregulation in microRNA expression is associated with alterations in immune functions in combat veterans with post-traumatic stress disorder. PLoS One 9(4):e94075
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethical Approval
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Tfilin, M., Turgeman, G. Interleukine-17 Administration Modulates Adult Hippocampal Neurogenesis and Improves Spatial Learning in Mice. J Mol Neurosci 69, 254–263 (2019). https://doi.org/10.1007/s12031-019-01354-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-019-01354-4