Transcriptomic evidence of a para-inflammatory state in the middle aged lumbar spinal cord

Galbavy, William; Lu, Yong; Kaczocha, Martin; Puopolo, Michelino; Liu, Lixin; Rebecchi, Mario J.

doi:10.1186/s12979-017-0091-6

Cited by 8 publications

(7 citation statements)

References 54 publications

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“…The major populations increased in ALS and aging were from monocyte and macrophage lineages. These changes are consistent with other studies that have found robust activation of these cells as part of the immune response during ALS disease progression and aging (Butovsky et al, 2012; Chiu et al, 2009; Galbavy et al, 2017; Kullberg, Aldskogius, & Ulfhake, 2001; Zondler et al, 2016). …”

Section: Resultssupporting

confidence: 91%

“…During the disease process, spinal cord‐derived microglia recruit inflammatory monocytes, and this process correlates with neuronal loss (Butovsky et al, 2012). During aging, immune cell infiltration also begins long before late‐stage degeneration with increases in T cell, microglial, and macrophage markers seen in the spinal cord during middle age (Galbavy et al, 2017; Galbavy, Kaczocha, Puopolo, Liu, & Rebecchi, 2015; Kullberg et al, 2001). One of the molecular mechanisms underlying this change may be the deacetylation of IFN regulatory factor 8 (IRF8) by SIRT1, which negatively regulates inflammatory cytokine production and affects macrophage infiltration during inflammation (Jia et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

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SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

et al. 2018

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SIRT1 is an NAD+‐dependent deacetylase that functions in a variety of cells and tissues to mitigate age‐associated diseases. However, it remains unknown if SIRT1 also acts to prevent pathological changes that accrue in motor neurons during aging and amyotrophic lateral sclerosis (ALS). In this study, we show that SIRT1 expression decreases in the spinal cord of wild‐type mice during normal aging. Using mouse models either overexpressing or lacking SIRT1 in motor neurons, we found that SIRT1 slows age‐related degeneration of motor neurons’ presynaptic sites at neuromuscular junctions (NMJs). Transcriptional analysis of spinal cord shows an overlap of greater than 90% when comparing alterations during normal aging with changes during ALS, revealing a substantial upregulation in immune and inflammatory response genes and a downregulation of synaptic transcripts. In addition, overexpressing SIRT1 in motor neurons delays progression to end‐stage disease in high copy SOD1G93A mice. Thus, our findings suggest that there are parallels between ALS and aging, and interventions to impede aging may also slow the progression of this devastating disease.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

et al. 2018

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“…In the same line was the greater nitrite and urea concentration in SC mononuclear cell cultures from old compared with sex-matched young rats. This is fully consistent with findings in recently published studies by Galbavy et al (2015Galbavy et al ( , 2017. In old rats, differently from Arg-1 expression, which was slightly, but not significantly greater in male rat SC, iNOS expression was markedly greater in their SC, so that iNOS/Arg-1 mRNA expression ratio was more shifted towards iNOS in males compared with females.…”

Section: Sex-based Age-associated Changes In Sc Inflammation Statesupporting

confidence: 92%

“…In contrast to the extensive research on inflammation-oxidation state in the aging brain, complementary studies in spinal cord (SC) are limited (Chung et al 2010;Galbavy et al 2015Galbavy et al , 2017. Given that the brain and SC are distinct CNS environments with very specialized functions (Baskar Jesudasan et al 2014), and that regional specificities in age-related changes in brain inflammatory cytokine profile have been observed (Xie et al 2003), on one hand, and that age-associated increase in the frequency of neurodegenerative phenomena in SC has been reported, on the other (Saito and Murayama 2000;Schmidt et al 2001), it is clear that analysis of SC inflammationoxidation state could be important.…”

Section: Introductionmentioning

confidence: 99%

Sex as a determinant of age-related changes in rat spinal cord inflammation-oxidation state

et al. 2017

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To close the gap in our knowledge of sex influence on age-related changes in inflammation-oxidation state in spinal cord (SC) relevant to inflammation/oxidative-stress associated neuropathologies, 2-3 month-old (young) and 18-20 month-old (old) rats, exhibiting increased level of IL-6, a commonly used marker of inflamm-aging, were examined for inflammatory/redox status, and the underlying regulatory networks' molecules expression. With age, rat SC microglia became sensitized ("primed"), while SC tissue shifted towards mild inflammatory state, with increased levels of proinflammatory IL-1β (key marker of microglial systemic inflammation-induced neurotoxicity), which was more prominent in males. This, most likely, reflected age- and sex-related impairment in the expression of CX3CR1, the receptor for fractalkine (CX3CL1), the soluble factor which regulates microglial activation and diminishes production of IL-1β (central for fractalkine neuroprotection). Considering that (i) age-related changes in SC IL-1β expression were not followed by complementary changes in SC IL-6 expression, and (ii) the reversal in the direction of the sex bias in circulating IL-6 level and SC IL-1β expression, it seems obvious that there are tissue-specific differences in the proinflammatory cytokine profile. Additionally, old male rat SC exhibited greater oxidative damage than female, reflecting, most likely, their lower capacity to maintain the pro-oxidant-antioxidant balance. In conclusion, these findings, apart from highlighting the significance of sex for age-associated changes in SC inflammation-oxidation, may be relevant for understating sex differences in human inflammation/oxidative-stress related SC diseases, and consequently, for optimizing their prevention/therapy.

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“…Previous studies have reported an increase in proinflammatory cytokines and glial activation in aging brain, as well as in rat spinal cord (Sparkman and Johnson 2008;Xie et al 2013;Galbavy et al 2017;Nacka-Aleksić et al 2017). We were interested in determining, whether there was an increase in inflammation in spinal cord from aging mice.…”

Section: Discussionmentioning

confidence: 99%

Molecular changes associated with spinal cord aging

et al. 2020

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Age-related muscle weakness and loss of muscle mass (sarcopenia) is a universal problem in the elderly. Our previous studies indicate that alpha motor neurons (α-MNs) play a critical role in this process. The goal of the current study is to uncover changes in the aging spinal cord that contribute to loss of innervation and the downstream degenerative processes that occur in skeletal muscle. The number of α-MNs is decreased in the spinal cord of wildtype mice during aging, beginning in middle age and reaching a 41% loss by 27 months of age. There is evidence for age-related loss of myelin and mild inflammation, including astrocyte and microglia activation and an increase in levels of sICAM-1. We identified changes in metabolites consistent with compromised neuronal viability, such as reduced levels of N-acetyl-aspartate. Cleaved caspase-3 is more abundant in spinal cord from old mice, suggesting that apoptosis contributes to neuronal loss. RNA-seq analysis revealed changes in the expression of a number of genes in spinal cord from old mice, in particular genes encoding extracellular matrix components (ECM) and a 172-fold increase in MMP-12 expression. Furthermore, blood-spinal cord barrier (BSCB) permeability is increased in old mice, which may contribute to alterations in spinal cord homeostasis and exacerbate neuronal distress. Together, these data show for the first time that the spinal cord undergoes significant changes during aging, including progressive α-MNs loss that is associated with low-grade inflammation, apoptosis, changes in ECM, myelination, and vascular permeability.

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Transcriptomic evidence of a para-inflammatory state in the middle aged lumbar spinal cord

Cited by 8 publications

References 54 publications

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

Sex as a determinant of age-related changes in rat spinal cord inflammation-oxidation state

Molecular changes associated with spinal cord aging

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