The detrimental effects of lipopolysaccharideinduced neuroinflammation on adult hippocampal neurogenesis depend on the duration of the pro-inflammatory response
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摘要
Adult hippocampal neurogenesis is a finely tuned process regulated by extrinsic factors. Neuroinflammation is a hallmark of several pathological conditions underlying dysregulation of neurogenesis. In animal models, lipopolysaccharide(LPS)-induced neuroinflammation leads to a neurogenic decrease mainly associated to the early inflammatory response. However, it is not well understood how the neuroinflammatory response progresses over time and if neurogenesis continues to be diminished during the late neuroinflammatory response. Moreover, it is unknown if repeated intermittent administration of LPS along time induces a greater reduction in neurogenesis. We administered one single intraperitoneal injection of LPS or saline or four repeated injections(one per week) of LPS or saline to young-adult mice. A cohort of new cells was labeled with three 5-bromo-2-deoxyuridine injections(one per day) 4 days after the last LPS injection. We evaluated systemic and neuroinflammation-associated parameters and compared the effects of the late neuroinflammatory response on neurogenesis induced by each protocol. Our results show that 1) a single LPS injection leads to a late pro-inflammatory response characterized by microglial activation, moderate astrocytic reaction and increased interleukin-6 levels. This response correlates in time with decreased neurogenesis and 2) a repeated intermittent injection of LPS does not elicit a late pro-inflammatory response although activated microglia persists. The latter profile is not accompanied by a continued longterm hippocampal neurogenic decrease. Hereby, we provide evidence that the neuroinflammatory response is a dynamic process that progresses in a milieu-dependent manner and does not necessarily lead to a neurogenic decrease, highlighting the complex interaction between the immune system and neurogenesis.
Adult hippocampal neurogenesis is a finely tuned process regulated by extrinsic factors. Neuroinflammation is a hallmark of several pathological conditions underlying dysregulation of neurogenesis. In animal models, lipopolysaccharide(LPS)-induced neuroinflammation leads to a neurogenic decrease mainly associated to the early inflammatory response. However, it is not well understood how the neuroinflammatory response progresses over time and if neurogenesis continues to be diminished during the late neuroinflammatory response. Moreover, it is unknown if repeated intermittent administration of LPS along time induces a greater reduction in neurogenesis. We administered one single intraperitoneal injection of LPS or saline or four repeated injections(one per week) of LPS or saline to young-adult mice. A cohort of new cells was labeled with three 5-bromo-2-deoxyuridine injections(one per day) 4 days after the last LPS injection. We evaluated systemic and neuroinflammation-associated parameters and compared the effects of the late neuroinflammatory response on neurogenesis induced by each protocol. Our results show that 1) a single LPS injection leads to a late pro-inflammatory response characterized by microglial activation, moderate astrocytic reaction and increased interleukin-6 levels. This response correlates in time with decreased neurogenesis and 2) a repeated intermittent injection of LPS does not elicit a late pro-inflammatory response although activated microglia persists. The latter profile is not accompanied by a continued longterm hippocampal neurogenic decrease. Hereby, we provide evidence that the neuroinflammatory response is a dynamic process that progresses in a milieu-dependent manner and does not necessarily lead to a neurogenic decrease, highlighting the complex interaction between the immune system and neurogenesis.
Adult hippocampal neurogenesis is a finely tuned process regulated by extrinsic factors. Neuroinflammation is a hallmark of several pathological conditions underlying dysregulation of neurogenesis. In animal models, lipopolysaccharide(LPS)-induced neuroinflammation leads to a neurogenic decrease mainly associated to the early inflammatory response. However, it is not well understood how the neuroinflammatory response progresses over time and if neurogenesis continues to be diminished during the late neuroinflammatory response. Moreover, it is unknown if repeated intermittent administration of LPS along time induces a greater reduction in neurogenesis. We administered one single intraperitoneal injection of LPS or saline or four repeated injections(one per week) of LPS or saline to young-adult mice. A cohort of new cells was labeled with three 5-bromo-2-deoxyuridine injections(one per day) 4 days after the last LPS injection. We evaluated systemic and neuroinflammation-associated parameters and compared the effects of the late neuroinflammatory response on neurogenesis induced by each protocol. Our results show that 1) a single LPS injection leads to a late pro-inflammatory response characterized by microglial activation, moderate astrocytic reaction and increased interleukin-6 levels. This response correlates in time with decreased neurogenesis and 2) a repeated intermittent injection of LPS does not elicit a late pro-inflammatory response although activated microglia persists. The latter profile is not accompanied by a continued longterm hippocampal neurogenic decrease. Hereby, we provide evidence that the neuroinflammatory response is a dynamic process that progresses in a milieu-dependent manner and does not necessarily lead to a neurogenic decrease, highlighting the complex interaction between the immune system and neurogenesis.
引文
Battista D,Ferrari CC,Gage FH,Pitossi FJ(2006)Neurogenic niche modulation by activated microglia:Transforming growth factorβincreases neurogenesis in the adult dentate gyrus.Eur J Neurosci23:83-93.
Ben Abdallah NM,Slomianka L,Vyssotski AL,Lipp HP(2010)Early age-related changes in adult hippocampal neurogenesis in C57 mice.Neurobiol Aging 31:151-161.
Bian Y,Zhao X,Li M,Zeng S,Zhao B(2013)Various roles of astrocytes during recovery from repeated exposure to different doses of lipopolysaccharide.Behav Brain Res 253:253-261.
Biesmans S,Meert TF,Bouwknecht JA,Acton PD,Davoodi N,De Haes P,Kuijlaars J,Langlois X,Matthews LJR,Ver Donck L,Hellings N,Nuydens R(2013)Systemic immune activation leads to neuroinflammation and sickness behavior in mice.Mediators Inflamm2013:271359.
Bignami A,Eng LF,Dahl D,Uyeda CT(1972)Localization of the glial fibrillary acidic protein in astrocytes by immunofluorescence.Brain Res 43:429-435.
Buffo A,Rolando C,Ceruti S(2010)Astrocytes in the damaged brain:Molecular and cellular insights into their reactive response and healing potential.Biochem Pharmacol 79:77-89.
Buttini M,Limonta S,Boddeke HWG(1996)Peripheral administration of lipopolysaccharide induces activation of microglial cells in rat brain.Neurochem Int 29:25-35.
Carpentier PA,Palmer TD(2009)Immune Influence on Adult Neural Stem Cell Regulation and Function.Neuron 64:79-92
Dantzer R,O’Connor JC,Freund GG,Johnson RW,Kelley KW(2008)From inflammation to sickness and depression:when the immune system subjugates the brain.Nat Rev Neurosci 9:46-56.
de Miranda AS,Zhang CJ,Katsumoto A,Teixeira AL(2017)Hippocampal adult neurogenesis:Does the immune system matter?J Neurol Sci 372:482-495
Ekdahl CT,Claasen J-H,Bonde S,Kokaia Z,Lindvall O(2003)Inflammation is detrimental for neurogenesis in adult brain.Proc Natl Acad Sci U S A 100:13632-13637.
Encinas JM,Michurina T V.,Peunova N,Park JH,Tordo J,Peterson DA,Fishell G,Koulakov A,Enikolopov G(2011)Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus.Cell Stem Cell 8:566-579.
Fan LW,Pang Y(2017)Dysregulation of neurogenesis by neuroinflammation:key differences in neurodevelopmental and neurological disorders.Neural Regen Res 12:366-371.
Fujioka H,Akema T(2010)Lipopolysaccharide acutely inhibits proliferation of neural precursor cells in the dentate gyrus in adult rats.Brain Res 1352:35-42.
Gon?alves JT,Schafer ST,Gage FH(2016)Adult Neurogenesis in the Hippocampus:From Stem Cells to Behavior.Cell 167:897-914.
Hanisch UK,Kettenmann H(2007)Microglia:Active sensor and versatile effector cells in the normal and pathologic brain.Nat Neurosci10:1387-1394.
Heneka MT,Rodríguez JJ,Verkhratsky A(2010)Neuroglia in neurodegeneration.Brain Res Rev 63:189-211.
Ito D,Imai Y,Ohsawa K,Nakajima K,Fukuuchi Y,Kohsaka S(1998)Microglia-specific localisation of a novel calcium binding protein,Iba1.Mol Brain Res 57:1-9.
Jurgens HA,Johnson RW(2012)Dysregulated neuronal-microglial cross-talk during aging,stress and inflammation.Exp Neurol 233:40-48.
Kohman RA,Rhodes JS(2013)Neurogenesis,inflammation and behavior.Brain Behav Immun 27:22-32.
Kuno R,Yoshida Y,Nitta A,Nabeshima T,Wang J,Sonobe Y,Kawanokuchi J,Takeuchi H,Mizuno T,Suzumura A(2006)The role of TNF-alpha and its receptors in the production of NGF and GDNFby astrocytes.Brain Res 1116:12-18.
Littlefield AM,Setti SE,Priester C,Kohman RA(2015)Voluntary exercise attenuates LPS-induced reductions in neurogenesis and increases microglia expression of a proneurogenic phenotype in aged mice.J Neuroinflammation 12:138.
Lopes PC(2016)LPS and neuroinflammation:a matter of timing.Inflammopharmacology 24:291-293.
Lynch MA(2009)The multifaceted profile of activated microglia.Mol Neurobiol 40:139-156.
Mathieu P,Battista D,Depino A,Roca V,Graciarena M,Pitossi F(2010)The more you have,the less you get:The functional role of inflammation on neuronal differentiation of endogenous and transplanted neural stem cells in the adult brain.J Neurochem 112:1368-1385.
Melo-Salas MS,Pérez-Domínguez M,Zepeda A(2018)Systemic Inflammation Impairs Proliferation of Hippocampal Type 2 Intermediate Precursor Cells.Cell Mol Neurobiol 38:1517-1528.
Min KJ,Yang M,Kim SU,Jou I,Joe E(2006)Astrocytes induce hemeoxygenase-1 expression in microglia:a feasible mechanism for preventing excessive brain inflammation.J Neurosci 26:1880-1887.
Monje ML,Toda H,Palmer TD(2003)Inflammatory Blockade Restores Adult Hippocampal Neurogenesis.Science 302:1760-1765.
Nakanishi M,Niidome T,Matsuda S,Akaike A,Kihara T,Sugimoto H(2007)Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells.Eur J Neurosci 25:649-658.
Pardon MC(2015)Lipopolysaccharide hyporesponsiveness:Protective or damaging response to the brain?Rom J Morphol Embryol 56:903-913.
Pérez-Domínguez M,Tovar-y-Romo LB,Zepeda A(2017)Neuroinflammation and physical exercise as modulators of adult hippocampal neural precursor cell behavior.Rev Neurosci 29:1-20.
Perry VH,Cunningham C,Holmes C(2007)Systemic infections and inflammation affect chronic neurodegeneration.Nat Rev Immunol7:161-167.
Qin L,Wu X,Block ML,Liu Y,Breese GR,Knapp DJ,Crews FT(2007)Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration.Glia 55:453-462.
Skelly DT,Hennessy E,Dansereau MA,Cunningham C(2013)ASystematic Analysis of the Peripheral and CNS Effects of Systemic LPS,IL-1Β,TNF-αand IL-6 Challenges in C57BL/6 Mice.PLoS One8:e69123.
Sofroniew MV(2009)Molecular dissection of reactive astrogliosis and glial scar formation.Trends Neurosci 32:638-647.
Sofroniew M V(2015)Astrogliosis.Cold Spring Harb Perpect Biol7:a020420
Tanaka T,Oh-hashi K,Shitara H,Hirata Y,Kiuchi K(2008)NF-κB independent signaling pathway is responsible for LPS-induced GDNFgene expression in primary rat glial cultures.Neurosci Lett 431:262-267.
Turrin NP,Gayle D,Ilyin SE,Flynn MC,Langhans W,Schwartz GJ,Plata-Salamán CR(2001)Pro-inflammatory and anti-inflammatory cytokine mRNA induction in the periphery and brain following intraperitoneal administration of bacterial lipopolysaccharide.Brain Res Bull 54:443-453.
Valero J,Mastrella G,Neiva I,Sánchez S,Malva JO(2014)Long-term effects of an acute and systemic administration of LPS on adult neurogenesis and spatial memory.Front Neurosci 8:83.
Vallières L,Campbell IL,Gage FH,Sawchenko PE(2002)Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6.J Neurosci 22:486-492.
Whitney NP,Eidem TM,Peng H,Huang Y,Zheng JC(2009)Inflammation mediates varying effects in neurogenesis:relevance to the pathogenesis of brain injury and neurodegenerative disorders.JNeurochem 108:1343-1359.
Wilhelmsson U,Bushong EA,Price DL,Smarr BL,Phung V,Terada M,Ellisman MH,Pekny M(2006)Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury.Proc Natl Acad Sci U S A 103:17513-17518.
Wu CW,Chang YT,Yu L,Chen HI,Jen CJ,Wu SY,Lo CP,Kuo YM(2008)Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice.J Appl Physiol 105:1585-1594.
Wu CW,Chen YC,Yu L,Chen HI,Jen CJ,Huang AM,Tsai HJ,Chang YT,Kuo YM(2007)Treadmill exercise counteracts the suppressive effects of peripheral lipopolysaccharide on hippocampal neurogenesis and learning and memory.J Neurochem 103:2471-2481.
Zonis S,Ljubimov VA,Mahgerefteh M,Pechnick RN,Wawrowsky K,Chesnokova V(2013)p21Cip restrains hippocampal neurogenesis and protects neuronal progenitors from apoptosis during acute systemic inflammation.Hippocampus 23:1383-1394.
Ben Abdallah NM,Slomianka L,Vyssotski AL,Lipp HP(2010)Early age-related changes in adult hippocampal neurogenesis in C57 mice.Neurobiol Aging 31:151-161.
Bian Y,Zhao X,Li M,Zeng S,Zhao B(2013)Various roles of astrocytes during recovery from repeated exposure to different doses of lipopolysaccharide.Behav Brain Res 253:253-261.
Biesmans S,Meert TF,Bouwknecht JA,Acton PD,Davoodi N,De Haes P,Kuijlaars J,Langlois X,Matthews LJR,Ver Donck L,Hellings N,Nuydens R(2013)Systemic immune activation leads to neuroinflammation and sickness behavior in mice.Mediators Inflamm2013:271359.
Bignami A,Eng LF,Dahl D,Uyeda CT(1972)Localization of the glial fibrillary acidic protein in astrocytes by immunofluorescence.Brain Res 43:429-435.
Buffo A,Rolando C,Ceruti S(2010)Astrocytes in the damaged brain:Molecular and cellular insights into their reactive response and healing potential.Biochem Pharmacol 79:77-89.
Buttini M,Limonta S,Boddeke HWG(1996)Peripheral administration of lipopolysaccharide induces activation of microglial cells in rat brain.Neurochem Int 29:25-35.
Carpentier PA,Palmer TD(2009)Immune Influence on Adult Neural Stem Cell Regulation and Function.Neuron 64:79-92
Dantzer R,O’Connor JC,Freund GG,Johnson RW,Kelley KW(2008)From inflammation to sickness and depression:when the immune system subjugates the brain.Nat Rev Neurosci 9:46-56.
de Miranda AS,Zhang CJ,Katsumoto A,Teixeira AL(2017)Hippocampal adult neurogenesis:Does the immune system matter?J Neurol Sci 372:482-495
Ekdahl CT,Claasen J-H,Bonde S,Kokaia Z,Lindvall O(2003)Inflammation is detrimental for neurogenesis in adult brain.Proc Natl Acad Sci U S A 100:13632-13637.
Encinas JM,Michurina T V.,Peunova N,Park JH,Tordo J,Peterson DA,Fishell G,Koulakov A,Enikolopov G(2011)Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus.Cell Stem Cell 8:566-579.
Fan LW,Pang Y(2017)Dysregulation of neurogenesis by neuroinflammation:key differences in neurodevelopmental and neurological disorders.Neural Regen Res 12:366-371.
Fujioka H,Akema T(2010)Lipopolysaccharide acutely inhibits proliferation of neural precursor cells in the dentate gyrus in adult rats.Brain Res 1352:35-42.
Gon?alves JT,Schafer ST,Gage FH(2016)Adult Neurogenesis in the Hippocampus:From Stem Cells to Behavior.Cell 167:897-914.
Hanisch UK,Kettenmann H(2007)Microglia:Active sensor and versatile effector cells in the normal and pathologic brain.Nat Neurosci10:1387-1394.
Heneka MT,Rodríguez JJ,Verkhratsky A(2010)Neuroglia in neurodegeneration.Brain Res Rev 63:189-211.
Ito D,Imai Y,Ohsawa K,Nakajima K,Fukuuchi Y,Kohsaka S(1998)Microglia-specific localisation of a novel calcium binding protein,Iba1.Mol Brain Res 57:1-9.
Jurgens HA,Johnson RW(2012)Dysregulated neuronal-microglial cross-talk during aging,stress and inflammation.Exp Neurol 233:40-48.
Kohman RA,Rhodes JS(2013)Neurogenesis,inflammation and behavior.Brain Behav Immun 27:22-32.
Kuno R,Yoshida Y,Nitta A,Nabeshima T,Wang J,Sonobe Y,Kawanokuchi J,Takeuchi H,Mizuno T,Suzumura A(2006)The role of TNF-alpha and its receptors in the production of NGF and GDNFby astrocytes.Brain Res 1116:12-18.
Littlefield AM,Setti SE,Priester C,Kohman RA(2015)Voluntary exercise attenuates LPS-induced reductions in neurogenesis and increases microglia expression of a proneurogenic phenotype in aged mice.J Neuroinflammation 12:138.
Lopes PC(2016)LPS and neuroinflammation:a matter of timing.Inflammopharmacology 24:291-293.
Lynch MA(2009)The multifaceted profile of activated microglia.Mol Neurobiol 40:139-156.
Mathieu P,Battista D,Depino A,Roca V,Graciarena M,Pitossi F(2010)The more you have,the less you get:The functional role of inflammation on neuronal differentiation of endogenous and transplanted neural stem cells in the adult brain.J Neurochem 112:1368-1385.
Melo-Salas MS,Pérez-Domínguez M,Zepeda A(2018)Systemic Inflammation Impairs Proliferation of Hippocampal Type 2 Intermediate Precursor Cells.Cell Mol Neurobiol 38:1517-1528.
Min KJ,Yang M,Kim SU,Jou I,Joe E(2006)Astrocytes induce hemeoxygenase-1 expression in microglia:a feasible mechanism for preventing excessive brain inflammation.J Neurosci 26:1880-1887.
Monje ML,Toda H,Palmer TD(2003)Inflammatory Blockade Restores Adult Hippocampal Neurogenesis.Science 302:1760-1765.
Nakanishi M,Niidome T,Matsuda S,Akaike A,Kihara T,Sugimoto H(2007)Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells.Eur J Neurosci 25:649-658.
Pardon MC(2015)Lipopolysaccharide hyporesponsiveness:Protective or damaging response to the brain?Rom J Morphol Embryol 56:903-913.
Pérez-Domínguez M,Tovar-y-Romo LB,Zepeda A(2017)Neuroinflammation and physical exercise as modulators of adult hippocampal neural precursor cell behavior.Rev Neurosci 29:1-20.
Perry VH,Cunningham C,Holmes C(2007)Systemic infections and inflammation affect chronic neurodegeneration.Nat Rev Immunol7:161-167.
Qin L,Wu X,Block ML,Liu Y,Breese GR,Knapp DJ,Crews FT(2007)Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration.Glia 55:453-462.
Skelly DT,Hennessy E,Dansereau MA,Cunningham C(2013)ASystematic Analysis of the Peripheral and CNS Effects of Systemic LPS,IL-1Β,TNF-αand IL-6 Challenges in C57BL/6 Mice.PLoS One8:e69123.
Sofroniew MV(2009)Molecular dissection of reactive astrogliosis and glial scar formation.Trends Neurosci 32:638-647.
Sofroniew M V(2015)Astrogliosis.Cold Spring Harb Perpect Biol7:a020420
Tanaka T,Oh-hashi K,Shitara H,Hirata Y,Kiuchi K(2008)NF-κB independent signaling pathway is responsible for LPS-induced GDNFgene expression in primary rat glial cultures.Neurosci Lett 431:262-267.
Turrin NP,Gayle D,Ilyin SE,Flynn MC,Langhans W,Schwartz GJ,Plata-Salamán CR(2001)Pro-inflammatory and anti-inflammatory cytokine mRNA induction in the periphery and brain following intraperitoneal administration of bacterial lipopolysaccharide.Brain Res Bull 54:443-453.
Valero J,Mastrella G,Neiva I,Sánchez S,Malva JO(2014)Long-term effects of an acute and systemic administration of LPS on adult neurogenesis and spatial memory.Front Neurosci 8:83.
Vallières L,Campbell IL,Gage FH,Sawchenko PE(2002)Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6.J Neurosci 22:486-492.
Whitney NP,Eidem TM,Peng H,Huang Y,Zheng JC(2009)Inflammation mediates varying effects in neurogenesis:relevance to the pathogenesis of brain injury and neurodegenerative disorders.JNeurochem 108:1343-1359.
Wilhelmsson U,Bushong EA,Price DL,Smarr BL,Phung V,Terada M,Ellisman MH,Pekny M(2006)Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury.Proc Natl Acad Sci U S A 103:17513-17518.
Wu CW,Chang YT,Yu L,Chen HI,Jen CJ,Wu SY,Lo CP,Kuo YM(2008)Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice.J Appl Physiol 105:1585-1594.
Wu CW,Chen YC,Yu L,Chen HI,Jen CJ,Huang AM,Tsai HJ,Chang YT,Kuo YM(2007)Treadmill exercise counteracts the suppressive effects of peripheral lipopolysaccharide on hippocampal neurogenesis and learning and memory.J Neurochem 103:2471-2481.
Zonis S,Ljubimov VA,Mahgerefteh M,Pechnick RN,Wawrowsky K,Chesnokova V(2013)p21Cip restrains hippocampal neurogenesis and protects neuronal progenitors from apoptosis during acute systemic inflammation.Hippocampus 23:1383-1394.