The effect of intrauterine inflammation on mTOR signaling in mouse fetal brain.

Publisher: Wiley Subscription Services, Inc Country of Publication: United States NLM ID: 101300215 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-846X (Electronic) Linking ISSN: 19328451 NLM ISO Abbreviation: Dev Neurobiol Subsets: MEDLINE

Original Publication: Hoboken, NJ : Wiley Subscription Services, Inc.

Brain Diseases*/immunology ; Brain Diseases*/metabolism ; Brain Diseases*/pathology ; Cerebral Cortex*/immunology ; Cerebral Cortex*/metabolism ; Cerebral Cortex*/pathology ; Fetal Diseases*/immunology ; Fetal Diseases*/metabolism ; Fetal Diseases*/pathology ; Inflammation*/immunology ; Inflammation*/metabolism ; Inflammation*/pathology ; Microglia*/immunology ; Microglia*/metabolism; Fetal Development/*physiology ; Signal Transduction/*physiology ; TOR Serine-Threonine Kinases/*metabolism; Animals ; Disease Models, Animal ; Female ; Fetal Development/immunology ; Lipopolysaccharides/pharmacology ; Mice ; Pregnancy ; Signal Transduction/immunology

Fetuses exposed to an inflammatory environment are predisposed to long-term adverse neurological outcomes. However, the mechanism by which intrauterine inflammation (IUI) is responsible for abnormal fetal brain development is not fully understood. The mechanistic target of rapamycin (mTOR) signaling pathway is closely associated with fetal brain development. We hypothesized that mTOR signaling might be involved in fetal brain injury and malformation when fetuses are exposed to the IUI environment. A well-established IUI model was utilized by intrauterine injection of lipopolysaccharide (LPS) to explore the effect of IUI on mTOR signaling in mouse fetal brains. We found that microglia activation in LPS fetal brains was increased, as demonstrated by elevated Iba-1 protein level and immunofluorescence density. LPS fetal brains also showed reduced neuronal cell counts, decreased cell proliferation demonstrated by low Ki67-positive density, and elevated neuron apoptosis evidenced by high expression of cleaved Caspase 3. Furthermore, we found that mTOR signaling in LPS fetal brains was elevated at 2 hr after LPS treatment, declined at 6 hr and showed overall inhibition at 24 hr. In summary, our study revealed that LPS-induced IUI leads to increased activation of microglia cells, neuronal damage, and dynamic alterations in mTOR signaling in the mouse fetal brain. Our findings indicate that abnormal changes in mTOR signaling may underlie the development of future neurological complications in offspring exposed to prenatal IUI.
(© 2020 Wiley Periodicals LLC.)

Adams-Chapman, I., & Stoll, B. J. (2006). Neonatal infection and long-term neurodevelopmental outcome in the preterm infant. Current Opinion in Infectious Diseases, 19(3), 290-297. https://doi.org/10.1097/01.qco.0000224825.57976.87.
al-Haddad, B. J. S., Oler, E., Armistead, B., Elsayed, N. A., Weinberger, D. R., Bernier, R., … Adams Waldorf, K. M. (2019). The fetal origins of mental illness. American Journal of Obstetrics and Gynecology, 221(6), 549-562. https://doi.org/10.1016/j.ajog.2019.06.013.
Anblagan, D., Pataky, R., Evans, M. J., Telford, E. J., Serag, A., Sparrow, S., … Boardman, J. P. (2016). Association between preterm brain injury and exposure to chorioamnionitis during fetal life. Scientific Reports, 6, 37932. https://doi.org/10.1038/srep37932.
Benjamin, M. M. (1978). Outline of veterinary clinical pathology. Desmoins, IO: Iowa State University Press.
Brown, A. G., Maubert, M. E., Anton, L., Heiser, L. M., & Elovitz, M. A. (2019). The tracking of lipopolysaccharide through the feto-maternal compartment and the involvement of maternal TLR4 in inflammation-induced fetal brain injury. American Journal of Reproductive Immunology, 82(6), e13189. https://doi.org/10.1111/aji.13189.
Burd, I., Balakrishnan, B., & Kannan, S. (2012). Models of fetal brain injury, intrauterine inflammation, and preterm birth. American Journal of Reproductive Immunology, 67(4), 287-294. https://doi.org/10.1111/j.1600-0897.2012.01110.x.
Burd, I., Bentz, A. I., Chai, J., Gonzalez, J., Monnerie, H., Le Roux, P. D., … Elovitz, M. A. (2010). Inflammation-induced preterm birth alters neuronal morphology in the mouse fetal brain. Journal of Neuroscience Research, 88(9), 1872-1881. https://doi.org/10.1002/jnr.22368.
Cordeiro, C. N., Tsimis, M., & Burd, I. (2015). Infections and brain development. Obstetrical & Gynecological Survey, 70(10), 644-655. https://doi.org/10.1097/OGX.0000000000000236.
Elovitz, M. A., Wang, Z., Chien, E. K., Rychlik, D. F., & Phillippe, M. (2003). A new model for inflammation-induced preterm birth: The role of platelet-activating factor and Toll-like receptor-4. American Journal of Pathology, 163(5), 2103-2111. https://doi.org/10.1016/S0002-9440(10)63567-5.
Ernst, L. M., Gonzalez, J., Ofori, E., & Elovitz, M. (2010). Inflammation-induced preterm birth in a murine model is associated with increases in fetal macrophages and circulating erythroid precursors. Pediatric and Developmental Pathology, 13(4), 273-281. https://doi.org/10.2350/09-05-0649-OA.1.
Fricke, E. M., Elgin, T. G., Gong, H., Reese, J., Gibson-Corley, K. N., Weiss, R. M., … McElroy, S. J. (2018). Lipopolysaccharide-induced maternal inflammation induces direct placental injury without alteration in placental blood flow and induces a secondary fetal intestinal injury that persists into adulthood. American Journal of Reproductive Immunology, 79(5), e12816. https://doi.org/10.1111/aji.12816.
Goasdoue, K., Miller, S. M., Colditz, P. B., & Bjorkman, S. T. (2017). Review: The blood-brain barrier; protecting the developing fetal brain. Placenta, 54, 111-116. https://doi.org/10.1016/j.placenta.2016.12.005.
Huleihel, M., Golan, H., & Hallak, M. (2004). Intrauterine infection/inflammation during pregnancy and offspring brain damages: Possible mechanisms involved. Reproductive Biology and Endocrinology, 2, 17. https://doi.org/10.1186/1477-7827-2-17.
Jia, B., Zong, L. U., Lee, J. Y., Lei, J., Zhu, Y., Xie, H., … Burd, I. (2019). Maternal supplementation of low dose fluoride alleviates adverse perinatal outcomes following exposure to intrauterine inflammation. Scientific Reports, 9(1), 2575. https://doi.org/10.1038/s41598-018-38241-8.
Ka, M., Condorelli, G., Woodgett, J. R., & Kim, W. Y. (2014). mTOR regulates brain morphogenesis by mediating GSK3 signaling. Development, 141(21), 4076-4086. https://doi.org/10.1242/dev.108282.
Kaur, C., Rathnasamy, G., & Ling, E. A. (2017). Biology of microglia in the developing brain. Journal of Neuropathology and Experimental Neurology, 76(9), 736-753. https://doi.org/10.1093/jnen/nlx056.
Khandaker, G. M., Zimbron, J., Lewis, G., & Jones, P. B. (2013). Prenatal maternal infection, neurodevelopment and adult schizophrenia: A systematic review of population-based studies. Psychological Medicine, 43(2), 239-257. https://doi.org/10.1017/S0033291712000736.
Kim, C. J., Romero, R., Chaemsaithong, P., & Kim, J. S. (2015). Chronic inflammation of the placenta: Definition, classification, pathogenesis, and clinical significance. American Journal of Obstetrics and Gynecology, 213(4 Suppl), S53-S69. https://doi.org/10.1016/j.ajog.2015.08.041.
Kohmura, Y., Kirikae, T., Kirikae, F., Nakano, M., & Sato, I. (2000). Lipopolysaccharide (LPS)-induced intra-uterine fetal death (IUFD) in mice is principally due to maternal cause but not fetal sensitivity to LPS. Microbiology and Immunology, 44(11), 897-904. https://doi.org/10.1111/j.1348-0421.2000.tb02581.x.
Kopp, E. B., & Medzhitov, R. (1999). The Toll-receptor family and control of innate immunity. Current Opinion in Immunology, 11(1), 13-18. https://doi.org/10.1016/S0952-7915(99)80003-X.
Lee, J. Y., Song, H., Dash, O., Park, M., Shin, N. E., McLane, M. W., … Burd, I. (2019). Administration of melatonin for prevention of preterm birth and fetal brain injury associated with premature birth in a mouse model. American Journal of Reproductive Immunology, 82(3), e13151. https://doi.org/10.1111/aji.13151.
Lei, J., Zhong, W., Almalki, A., Zhao, H., Arif, H., Rozzah, R., … Burd, I. (2018). Maternal glucose supplementation in a murine model of chorioamnionitis alleviates dysregulation of autophagy in fetal brain. Reproductive Sciences, 25(8), 1175-1185. https://doi.org/10.1177/1933719117734321.
Levine, B., & Kroemer, G. (2019). Biological functions of autophagy genes: A disease perspective. Cell, 176(1-2), 11-42. https://doi.org/10.1016/j.cell.2018.09.048.
Leviton, A., Allred, E. N., Kuban, K. C. K., O'Shea, T. M., Paneth, N., Onderdonk, A. B., … Dammann, O. (2016). The development of extremely preterm infants born to women who had genitourinary infections during pregnancy. American Journal of Epidemiology, 183(1), 28-35. https://doi.org/10.1093/aje/kwv129.
Lipton, J. O., & Sahin, M. (2014). The neurology of mTOR. Neuron, 84(2), 275-291. https://doi.org/10.1016/j.neuron.2014.09.034.
Malaeb, S., & Dammann, O. (2009). Fetal inflammatory response and brain injury in the preterm newborn. Journal of Child Neurology, 24(9), 1119-1126. https://doi.org/10.1177/0883073809338066.
Meyer, U., Feldon, J., Schedlowski, M., & Yee, B. K. (2006). Immunological stress at the maternal-foetal interface: A link between neurodevelopment and adult psychopathology. Brain, Behavior, and Immunity, 20(4), 378-388. https://doi.org/10.1016/j.bbi.2005.11.003.
Ng, S., Wu, Y. T., Chen, B., Zhou, J., & Shen, H. M. (2011). Impaired autophagy due to constitutive mTOR activation sensitizes TSC2-null cells to cell death under stress. Autophagy, 7(10), 1173-1186. https://doi.org/10.4161/auto.7.10.16681.
Novak, C. M., Ozen, M., McLane, M., Alqutub, S., Lee, J. Y., Lei, J., & Burd, I. (2018). Progesterone improves perinatal neuromotor outcomes in a mouse model of intrauterine inflammation via immunomodulation of the placenta. American Journal of Reproductive Immunology, 79(5), e12842. https://doi.org/10.1111/aji.12842.
O'Loughlin, E., Pakan, J. M. P., Yilmazer-Hanke, D., & McDermott, K. W. (2017). Acute in utero exposure to lipopolysaccharide induces inflammation in the pre- and postnatal brain and alters the glial cytoarchitecture in the developing amygdala. Journal of Neuroinflammation, 14(1), 212. https://doi.org/10.1186/s12974-017-0981-8.
Papadakis, M., Hadley, G., Xilouri, M., Hoyte, L. C., Nagel, S., McMenamin, M. M., … Buchan, A. M. (2013). Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy. Nature Medicine, 19(3), 351-357. https://doi.org/10.1038/nm.3097.
Sadowska, G. B., Chen, X., Zhang, J., Lim, Y. P., Cummings, E. E., Makeyev, O., … Stonestreet, B. S. (2015). Interleukin-1beta transfer across the blood-brain barrier in the ovine fetus. Journal of Cerebral Blood Flow and Metabolism, 35(9), 1388-1395. https://doi.org/10.1038/jcbfm.2015.134.
Saxton, R. A., & Sabatini, D. M. (2017). mTOR signaling in growth, metabolism, and disease. Cell, 168(6), 960-976. https://doi.org/10.1016/j.cell.2017.02.004.
Shatrov, J. G., Birch, S. C., Lam, L. T., Quinlivan, J. A., McIntyre, S., & Mendz, G. L. (2010). Chorioamnionitis and cerebral palsy: A meta-analysis. Obstetrics and Gynecology, 116(2 Pt 1), 387-392. https://doi.org/10.1097/AOG.0b013e3181e90046.
Shi, Z., Ma, L., Luo, K., Bajaj, M., Chawla, S., Natarajan, G., … Tan, S. (2017). Chorioamnionitis in the development of cerebral palsy: A meta-analysis and systematic. Review. Pediatrics, 139(6), 1-15. https://doi.org/10.1542/peds.2016-3781.
Simões, L. R., Sangiogo, G., Tashiro, M. H., Generoso, J. S., Faller, C. J., Dominguini, D., … Barichello, T. (2018). Maternal immune activation induced by lipopolysaccharide triggers immune response in pregnant mother and fetus, and induces behavioral impairment in adult rats. Journal of Psychiatric Research, 100, 71-83. https://doi.org/10.1016/j.jpsychires.2018.02.007.
Srivastava, I. N., Shperdheja, J., Baybis, M., Ferguson, T., & Crino, P. B. (2016). mTOR pathway inhibition prevents neuroinflammation and neuronal death in a mouse model of cerebral palsy. Neurobiology of Diseases, 85, 144-154. https://doi.org/10.1016/j.nbd.2015.10.001.
Switon, K., Kotulska, K., Janusz-Kaminska, A., Zmorzynska, J., & Jaworski, J. (2017). Molecular neurobiology of mTOR. Neuroscience, 341, 112-153. https://doi.org/10.1016/j.neuroscience.2016.11.017.
Takei, N., & Nawa, H. (2014). mTOR signaling and its roles in normal and abnormal brain development. Frontiers in Molecular Neuroscience, 7, 28. https://doi.org/10.3389/fnmol.2014.00028.
Tweedell, A., Mulligan, K. X., Martel, J. E., Chueh, F. Y., Santomango, T., & McGuinness, O. P. (2011). Metabolic response to endotoxin in vivo in the conscious mouse: Role of interleukin-6. Metabolism, 60(1), 92-98. https://doi.org/10.1016/j.metabol.2009.12.022.
Wu, D., Lei, J., Jia, B., Xie, H., Zhu, Y., Xu, J., … Burd, I. (2018). In vivo assessment of the placental anatomy and perfusion in a mouse model of intrauterine inflammation. Journal of Magnetic Resonance Imaging, 47(5), 1260-1267. https://doi.org/10.1002/jmri.25867.
Wu, Y. W., & Colford, J. M., Jr. (2000). Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis. JAMA, 284(11), 1417-1424. https://doi.org/10.1001/jama.284.11.1417.
Yanay, O., Bailey, A. L., Kernan, K., Zimmerman, J. J., & Osborne, W. R. (2015). Effects of exendin-4, a glucagon like peptide-1 receptor agonist, on neutrophil count and inflammatory cytokines in a rat model of endotoxemia. Journal of Inflammation Research, 8, 129-135. https://doi.org/10.2147/JIR.S84993.

International Johns Hopkins Integrated Research Center for Fetal Medicine Fund

Keywords: fetal neurodevelopment; intrauterine inflammation; mTOR signaling

0 (Lipopolysaccharides)
EC 2.7.1.1 (mTOR protein, mouse)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)

Date Created: 20200426 Date Completed: 20210618 Latest Revision: 20211204

20231215

10.1002/dneu.22755

32333505