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2. Sequential activation of microglia and astrocyte cytokine expression precedes increased iba-1 or GFAP immunoreactivity following systemic immune challenge

Author

Norden, Diana M., Trojanowski, Paige J., Villanueva, Emmanuel, Navarro González De Mesa, Elisa, Godbout, Jonathan P., Norden, Diana M., Trojanowski, Paige J., Villanueva, Emmanuel, Navarro González De Mesa, Elisa, and Godbout, Jonathan P.

Abstract

Activation of the peripheral immune system elicits a coordinated response from the central nervous system. Key to this immune to brain communication is that glia, microglia, and astrocytes, interpret and propagate inflammatory signals in the brain that influence physiological and behavioral responses. One issue in glial biology is that morphological analysis alone is used to report on glial activation state. Therefore, our objective was to compare behavioral responses after in vivo immune (lipopolysaccharide, LPS) challenge to glial specific mRNA and morphological profiles. Here, LPS challenge induced an immediate but transient sickness response with decreased locomotion and social interaction. Corresponding with active sickness behavior (2-12 h), inflammatory cytokine mRNA expression was elevated in enriched microglia and astrocytes. Although proinflammatory cytokine expression in microglia peaked 2-4 h after LPS, astrocyte cytokine, and chemokine induction was delayed and peaked at 12 h. Morphological alterations in microglia (Iba-1(+)) and astrocytes (GFAP(+)), however, were undetected during this 2-12 h timeframe. Increased Iba-1 immunoreactivity and de-ramified microglia were evident 24 and 48 h after LPS but corresponded to the resolution phase of activation. Morphological alterations in astrocytes were undetected after LPS. Additionally, glial cytokine expression did not correlate with morphology after four repeated LPS injections. In fact, repeated LPS challenge was associated with immune and behavioral tolerance and a less inflammatory microglial profile compared with acute LPS challenge. Overall, induction of glial cytokine expression was sequential, aligned with active sickness behavior, and preceded increased Iba-1 or GFAP immunoreactivity after LPS challenge, Depto. de Bioquímica y Biología Molecular, Fac. de Medicina, TRUE, pub

Published
2024

19. Kistimonas alittae sp. nov., a gammaproteobacterium isolated from the marine annelid Alitta succinea

Author

Ellis, J. Christopher, primary, Thomas, Michelle Suhan, additional, Lawson, Paul A., additional, Patel, Nisha B., additional, Faircloth, Whitney, additional, Hayes, Stephen E., additional, Linton, Emily E., additional, Norden, Diana M., additional, Severenchuk, Irina S., additional, West, Caitlin H., additional, Brown, James W., additional, Plante, Rebecca G., additional, and Plante, Craig J., additional

Published
2019
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20. The Alarmin HMGB1 Mediates Age-Induced Neuroinflammatory Priming

Author

Fonken, Laura K., primary, Frank, Matthew G., additional, Kitt, Meagan M., additional, D'Angelo, Heather M., additional, Norden, Diana M., additional, Weber, Michael D., additional, Barrientos, Ruth M., additional, Godbout, Jonathan P., additional, Watkins, Linda R., additional, and Maier, Steven F., additional

Published
2016
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22. Microglia of the Aged Brain: Primed to be Activated and Resistant to Regulation

Author

Norden, Diana M. and Godbout, Jonathan P.

Subjects
Inflammation, Aging, Animals, Brain, Humans, Microglia, Article, Immunity, Innate
Abstract

Innate immunity within the central nervous system (CNS) is primarily provided by resident microglia. Microglia are pivotal in immune surveillance and also facilitate the co-ordinated responses between the immune system and the brain. For example, microglia interpret and propagate inflammatory signals that are initiated in the periphery. This transient microglial activation helps mount the appropriate physiological and behavioural response following peripheral infection. With normal ageing, however, microglia develop a more inflammatory phenotype. For instance, in several models of ageing there are increased pro-inflammatory cytokines in the brain and increased expression of inflammatory receptors on microglia. This increased inflammatory status of microglia with ageing is referred to as primed, reactive or sensitized. A modest increase in the inflammatory profile of the CNS and altered microglial function in ageing has behavioural and cognitive consequences. Nonetheless, there are major differences in microglial biology between young and old age when the immune system is challenged and microglia are activated. In this context, microglial activation is amplified and prolonged in the aged brain compared with adults. The cause of this amplified microglial activation may be related to impairments in several key regulatory systems with age that make it more difficult to resolve microglial activation. The consequences of impaired regulation and microglial hyper-activation following immune challenge are exaggerated neuroinflammation, sickness behaviour, depressive-like behaviour and cognitive deficits. Therefore the purpose of this review is to discuss the current understanding of age-associated microglial priming, consequences of priming and reactivity, and the impairments in regulatory systems that may underlie these age-related deficits.

Published
2013

23. Sequential activation of microglia and astrocyte cytokine expression precedes increased iba-1 or GFAP immunoreactivity following systemic immune challenge

Author

Norden, Diana M., Trojanowski, Paige J., Villanueva, Emmanuel, Navarro González De Mesa, Elisa, Godbout, Jonathan P., Norden, Diana M., Trojanowski, Paige J., Villanueva, Emmanuel, Navarro González De Mesa, Elisa, and Godbout, Jonathan P.

Abstract

Activation of the peripheral immune system elicits a coordinated response from the central nervous system. Key to this immune to brain communication is that glia, microglia, and astrocytes, interpret and propagate inflammatory signals in the brain that influence physiological and behavioral responses. One issue in glial biology is that morphological analysis alone is used to report on glial activation state. Therefore, our objective was to compare behavioral responses after in vivo immune (lipopolysaccharide, LPS) challenge to glial specific mRNA and morphological profiles. Here, LPS challenge induced an immediate but transient sickness response with decreased locomotion and social interaction. Corresponding with active sickness behavior (2-12 h), inflammatory cytokine mRNA expression was elevated in enriched microglia and astrocytes. Although proinflammatory cytokine expression in microglia peaked 2-4 h after LPS, astrocyte cytokine, and chemokine induction was delayed and peaked at 12 h. Morphological alterations in microglia (Iba-1(+)) and astrocytes (GFAP(+)), however, were undetected during this 2-12 h timeframe. Increased Iba-1 immunoreactivity and de-ramified microglia were evident 24 and 48 h after LPS but corresponded to the resolution phase of activation. Morphological alterations in astrocytes were undetected after LPS. Additionally, glial cytokine expression did not correlate with morphology after four repeated LPS injections. In fact, repeated LPS challenge was associated with immune and behavioral tolerance and a less inflammatory microglial profile compared with acute LPS challenge. Overall, induction of glial cytokine expression was sequential, aligned with active sickness behavior, and preceded increased Iba-1 or GFAP immunoreactivity after LPS challenge, Depto. de Bioquímica y Biología Molecular, Fac. de Medicina, TRUE, pub

Published
2015

26. INFILTRATION OF MACROPHAGES PROMOTES INFLAMMATION RAPIDLY AT EPICENTER AND REMOTE REGIONS AFTER THORACIC SCI.

Author

Norden, Diana M., Faw, Timothy D., McKim, Daniel, Deibert, Rochelle, Fisher, Lesley C., Sheridan, John F., Godbout, Jonathan P., and Basso, D. Michele

Subjects
*NEUTROPHILS, *MACROPHAGES, *SPINAL cord injuries
Abstract

Spinal cord injury (SCI) produces a toxic inflammatory microenvironment that negatively affects plasticity and recovery. Recently we showed that glial activation and infiltration of bone-marrow derived myeloid cells extends past the epicenter and through remote areas of the lumbar cord after thoracic SCI. Recruitment of monocytes into intact regions of the lumbar cord may further impede locomotor rehabilitation depending on their activation profile. Therefore, our objective was to compare the inflammatory profile of resident microglia and peripheral myeloid cells after SCI. GFP + bone marrow chimeras received a moderate mid-thoracic contusion injury and trafficking of myeloid cells was determined 1-7 days later. FAC sorting showed that both neutrophils and macrophages infiltrated the epicenter and lumbar cord in a similar time frame. Through 7 days, the number of neutrophils was attenuated while the number of macrophages remained. These data suggest that macrophages play an important long-term role in influencing the microenvironment while neutrophils act acutely. Nanostring gene array identified a strong pro-inflammatory profile of infiltrating macrophages relative to microglia at both epicenter and lumbar sites. For instance, macrophages had elevated expression of inflammatory cytokines (IL-1β, IFNg), chemokines (CCL2, CXCL2), mediators (COX-1, MMP-9), and receptors (CCR2, Ly6C), and decreased expression of growth promoting genes (GDNF, BDNF). Such a high inflammatory potential of infiltrating macrophages within the central pattern generators for locomotion in the lumbar cord is likely to impede activity-dependent recovery. Importantly, macrophages recruited to the lumbar cord had elevated expression of genes associated with active trafficking (CCR2, L-selectin, MMP-9) compared to macrophages at the epicenter. Therefore, limiting active trafficking of macrophages into the lumbar cord identifies a novel target for SCI therapies to improve locomotion. [ABSTRACT FROM AUTHOR]

Published
2016

27. Astrocyte Mediated Regulation of Activated Microglia: Implications for Exaggerated Microglial Activation in Aged Mice Following Peripheral Inflammatory Challenge

Author

Norden, Diana M.

Subjects
Neurosciences, Behavioral Sciences
Abstract

Older individuals are at greater risk for infection and concomitant with this they have a higher frequency for developing neurobehavioral complications that negatively affect health and lifespan. For instance, otherwise innocuous infections are triggers for cognitive decline and the onset of depressive disorders in the elderly. This is a major issue because of the expansion of the elderly population. Neuroinflammation may be the key mechanism underlying the development of these neuropsychiatric disorders. Crosstalk between glial cells of the brain, including microglia and astrocytes, is normally involved in propagating inflammatory signals that are initiated in the periphery with infection. For example, microglia and astrocytes increased expression of inflammatory mediators following peripheral immune challenge in mice (Chapter 2). These increases in cytokine expression correlated to active sickness behavior in mice injected with the bacterial component lipopolysaccharide (LPS). Our work in aged mice, however, shows that aged microglia are hyperactive during an immune challenge and this results in prolonged neuroinflammation and the development of depression and cognitive impairments in the older mice. To limit inflammation, glial cells produce anti-inflammatory cytokines including interleukin (IL)-10. While IL-10 is also elevated in the aged brain following immune challenge, microglial activation still goes unresolved. Our studies show that there are dynamic interactions between microglia and astrocytes mediated by IL-10. For example, in adult mice astrocytes decrease pro-inflammatory activation following IL-10 signaling and also increase production of other regulatory molecules, including TGFb, that feedback on microglia (Chapter 3). Therefore, IL-10 may act as a critical anti-inflammatory mediator that attenuates neuroinflammation and prevents the development of neurobehavioral complications. In aged mice, however, astrocytes are more inflammatory and less sensitive to IL-10 regulation. Aged astrocytes had increased GFAP and vimentin expression, and decreased IL-10R surface expression compared to adults. Following acute immune challenge in vivo, adult astrocytes up-regulated IL-10R and TGFb mRNA. Aged astrocytes, however, failed to increase expression of these mediators. This lack of regulation by TGFb was associated with exaggerated expression of pro-inflammatory mediators in aged microglia. Last, active microglia cultured ex vivo with adult astrocytes reduced inflammatory markers while those cultured with aged astrocytes did not (Chapter 4). In summary, these novel data indicate that astrocytes have an important role in regulating microglia via TGFb signaling and that an impaired IL-10 response in aged astrocytes contributes to age-related deficits in the regulation of active microglia.

Published
2015

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