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Abstract # 3187 The effect of cytokine stimulation on astrocyte chemokine production and neutrophil chemoattraction
Abstracts / Brain, Behavior, and Immunity 76 (2019) e1–e43
the gut-brain axis. Obese humans and rhesus monkeys show deficits in executive function that are related to increased systemic inflammation and ameliorated by weight loss. Despite these links, it is unknown if systemic inflammation mediates lean muscle vs. visceral fat mass composition and executive function associations over time. Here, among 2197 males and 2469 females (47–81 years), from the UK Biobank database, we utilized non-linear differential equations stratified by gender to model 6-year changes in fluid intelligence over the course of 3 examinations. A structural equation mediation model interrogated how long-term changes in fluid intelligence were influenced by body composition (assessed by dual-energy X-ray absorptiometry; DEXA) and systemic inflammation (assessed by total white blood cell count). Age was covaried. Higher lean mass was strongly related to higher fluid intelligence scores in women (M = 4.95, b = 0.083, p < .001) and men (M = 7.31, b = 0.035, p < .001). Conversely, higher visceral fat mass was associated with worse scores in women (M = 4.95, b = 0.030, p < .001) and men (M = 7.31, b = 0.030, p < .001). Total white blood cell count mediated associations between fluid intelligence and lean mass (Female: 2.3%; Male: 5.4%) and fat mass (Female: 6.2%; Male: 9.2%). These results suggest that body composition strongly influences fluid intelligence, in part through modulating systemic inflammation. http://dx.doi.org/10.1016/j.bbi.2018.11.296
Abstract # 3187 The effect of cytokine stimulation on astrocyte chemokine production and neutrophil chemoattraction C. Walsh, M. Juda, S. Blackmore, A. Steelman University of Illinois, Animal Sciences, Edward R Madigan Laboratory, 1201 West Gregory Dr, Urbana, IL 61801, United States Systemic inflammation can exacerbate symptoms of many neurological diseases. This effect may be facilitated by either aberrant glial responses, or the trafficking of peripheral immune cells to the CNS. The later involves the production of chemokines, which themselves are capable of acting on neurons. In this study, primary astrocytes were stimulated with IL-1a, IL-1b, TNF, IL-1a/TNF or IL-1b/TNF and the levels of twenty-eight secreted chemokines were semiquantitatively determined using a Proteome Profiler array and densitometry. Pharmacological inhibitors were used to determine the effects of NFjB, p38 MAPK, JNK, and ERK1/2 pathway activation on chemokine production. Finally, neutrophil migration assays were performed to demonstrate functionality. Chemokine production was dependent on stimulation condition with IL-1a/TNF and IL-1b/ TNF challenge being the most efficient. The most abundantly produced chemokines were CCL2, CCL5, CCL12, CXCL1, CXCL5 and CXCL10. No single pharmacological inhibitor abolished chemokine secretion by astrocytes, implicating redundancy in the transcriptional activation at the level of the promotor. In agreement with the known capacity for CXCL1 and CXCL5 to promote neutrophil trafficking, cytokine treated astrocyte increased neutrophil migration. Intriguingly, pretreatment of astrocytes with a pharmacological inhibitor of TGF-bactivated kinase 1 ameliorated cytokine mediated neutrophil trafficking. Together, these results suggest that astrocytes likely contribute to trafficking of peripheral cells to the brain during systemic inflammation. http://dx.doi.org/10.1016/j.bbi.2018.11.297
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Abstract # 3188 Spinal cord injury perturbs circadian rhythms A.D. Gaudet a, L.K. Fonken b, M.T. Ayala a, E.M. Bateman a, W.E. Schleicher a, E.J. Smith a, H.M. D’Angelo a, S.F. Maier a, L.R. Watkins a a Department of Psychology & Neuroscience, 2860 Wilderness Place – UCB 603, Boulder, CO 80301, United States b Division of Pharmacology and Toxicology, University of Texas at Austin, United States
Spinal cord injury (SCI) can disrupt many physiological functions. The circadian system helps maintain homeostasis throughout the body by regulating daily rhythms in physiology and behavior. Circadian rhythms likely exist in all cell throughout the body, yet whether SCI alters daily rhythms remains under-studied. Here, we hypothesized that SCI in rats would disrupt several prominent circadian outputs including glucocorticoids, core temperature, activity, and circadian/inflammatory gene expression. Female and male rats received clinically relevant thoracic (T-) 8 moderate-to-severe contusion SCI (or laminectomy sham surgery). Circadian measures – including rhythms of plasma corticosterone, body temperature and activity (using small implanted transmitters), plasma glucose, and gene expression – were studied before and after surgery. First, we found that SCI disrupted intraspinal and peripheral rhythms of clock and inflammatory gene expression. Circadian rhythms in peripheral cells are entrained by ‘‘oscillatory factors”, including glucocorticoids, body temperature, and activity. SCI increased and disrupted rhythms of the major rodent glucocorticoid, corticosterone. Pre-surgery and sham rats displayed expected rhythms in activity and body temperature, whereas SCI rats had blunted daily rhythms in activity and body temperature. In parallel, SCI increased plasma glucose and liver expression of glucose metabolism genes. Our data show that moderate SCI in rats causes wide-ranging circadian dysfunction that is severe at acute time points and gradually recovers. Normalizing postSCI circadian rhythms could enhance recovery of homeostasis and quality-of-life. http://dx.doi.org/10.1016/j.bbi.2018.11.298
Abstract # 3189 Weighted gene co-expression network analysis suggests interferon activity is associated with depression severity M. Toups a, D. Arasappan b a
University of Texas Dell Medical School, 1701 Trinity St, Austin, TX 78712, United States b University of Texas Center for Computational Biology and Bioinformatics, United States To further the identification and treatment of patients with mood disorders having an immune component, we must identify the specific nature of immune processes associated with mood. We analyzed peripheral blood RNA sequencing data from the Depression Genes and Networks (DGN) Study using Weighted Gene Co-expression Network Analysis (WGCNA) from 441 adult subjects with a past or current diagnosis of Major Depressive Disorder. After filtering, 5778 genes were clustered in 19 modules. Overall, modules had weak clinical correlation; one module containing 63 genes showed the best correlation with scores on the 9-item Public–Health Questionnaire (PHQ-9) (r = 0.1, p = 0.03). This module was significantly enriched for the Gene Ontology Biological Process Type I Interferon Signaling (adjusted p? 0.001) and other pathways of
the gut-brain axis. Obese humans and rhesus monkeys show deficits in executive function that are related to increased systemic inflammation and ameliorated by weight loss. Despite these links, it is unknown if systemic inflammation mediates lean muscle vs. visceral fat mass composition and executive function associations over time. Here, among 2197 males and 2469 females (47–81 years), from the UK Biobank database, we utilized non-linear differential equations stratified by gender to model 6-year changes in fluid intelligence over the course of 3 examinations. A structural equation mediation model interrogated how long-term changes in fluid intelligence were influenced by body composition (assessed by dual-energy X-ray absorptiometry; DEXA) and systemic inflammation (assessed by total white blood cell count). Age was covaried. Higher lean mass was strongly related to higher fluid intelligence scores in women (M = 4.95, b = 0.083, p < .001) and men (M = 7.31, b = 0.035, p < .001). Conversely, higher visceral fat mass was associated with worse scores in women (M = 4.95, b = 0.030, p < .001) and men (M = 7.31, b = 0.030, p < .001). Total white blood cell count mediated associations between fluid intelligence and lean mass (Female: 2.3%; Male: 5.4%) and fat mass (Female: 6.2%; Male: 9.2%). These results suggest that body composition strongly influences fluid intelligence, in part through modulating systemic inflammation. http://dx.doi.org/10.1016/j.bbi.2018.11.296
Abstract # 3187 The effect of cytokine stimulation on astrocyte chemokine production and neutrophil chemoattraction C. Walsh, M. Juda, S. Blackmore, A. Steelman University of Illinois, Animal Sciences, Edward R Madigan Laboratory, 1201 West Gregory Dr, Urbana, IL 61801, United States Systemic inflammation can exacerbate symptoms of many neurological diseases. This effect may be facilitated by either aberrant glial responses, or the trafficking of peripheral immune cells to the CNS. The later involves the production of chemokines, which themselves are capable of acting on neurons. In this study, primary astrocytes were stimulated with IL-1a, IL-1b, TNF, IL-1a/TNF or IL-1b/TNF and the levels of twenty-eight secreted chemokines were semiquantitatively determined using a Proteome Profiler array and densitometry. Pharmacological inhibitors were used to determine the effects of NFjB, p38 MAPK, JNK, and ERK1/2 pathway activation on chemokine production. Finally, neutrophil migration assays were performed to demonstrate functionality. Chemokine production was dependent on stimulation condition with IL-1a/TNF and IL-1b/ TNF challenge being the most efficient. The most abundantly produced chemokines were CCL2, CCL5, CCL12, CXCL1, CXCL5 and CXCL10. No single pharmacological inhibitor abolished chemokine secretion by astrocytes, implicating redundancy in the transcriptional activation at the level of the promotor. In agreement with the known capacity for CXCL1 and CXCL5 to promote neutrophil trafficking, cytokine treated astrocyte increased neutrophil migration. Intriguingly, pretreatment of astrocytes with a pharmacological inhibitor of TGF-bactivated kinase 1 ameliorated cytokine mediated neutrophil trafficking. Together, these results suggest that astrocytes likely contribute to trafficking of peripheral cells to the brain during systemic inflammation. http://dx.doi.org/10.1016/j.bbi.2018.11.297
e39
Abstract # 3188 Spinal cord injury perturbs circadian rhythms A.D. Gaudet a, L.K. Fonken b, M.T. Ayala a, E.M. Bateman a, W.E. Schleicher a, E.J. Smith a, H.M. D’Angelo a, S.F. Maier a, L.R. Watkins a a Department of Psychology & Neuroscience, 2860 Wilderness Place – UCB 603, Boulder, CO 80301, United States b Division of Pharmacology and Toxicology, University of Texas at Austin, United States
Spinal cord injury (SCI) can disrupt many physiological functions. The circadian system helps maintain homeostasis throughout the body by regulating daily rhythms in physiology and behavior. Circadian rhythms likely exist in all cell throughout the body, yet whether SCI alters daily rhythms remains under-studied. Here, we hypothesized that SCI in rats would disrupt several prominent circadian outputs including glucocorticoids, core temperature, activity, and circadian/inflammatory gene expression. Female and male rats received clinically relevant thoracic (T-) 8 moderate-to-severe contusion SCI (or laminectomy sham surgery). Circadian measures – including rhythms of plasma corticosterone, body temperature and activity (using small implanted transmitters), plasma glucose, and gene expression – were studied before and after surgery. First, we found that SCI disrupted intraspinal and peripheral rhythms of clock and inflammatory gene expression. Circadian rhythms in peripheral cells are entrained by ‘‘oscillatory factors”, including glucocorticoids, body temperature, and activity. SCI increased and disrupted rhythms of the major rodent glucocorticoid, corticosterone. Pre-surgery and sham rats displayed expected rhythms in activity and body temperature, whereas SCI rats had blunted daily rhythms in activity and body temperature. In parallel, SCI increased plasma glucose and liver expression of glucose metabolism genes. Our data show that moderate SCI in rats causes wide-ranging circadian dysfunction that is severe at acute time points and gradually recovers. Normalizing postSCI circadian rhythms could enhance recovery of homeostasis and quality-of-life. http://dx.doi.org/10.1016/j.bbi.2018.11.298
Abstract # 3189 Weighted gene co-expression network analysis suggests interferon activity is associated with depression severity M. Toups a, D. Arasappan b a
University of Texas Dell Medical School, 1701 Trinity St, Austin, TX 78712, United States b University of Texas Center for Computational Biology and Bioinformatics, United States To further the identification and treatment of patients with mood disorders having an immune component, we must identify the specific nature of immune processes associated with mood. We analyzed peripheral blood RNA sequencing data from the Depression Genes and Networks (DGN) Study using Weighted Gene Co-expression Network Analysis (WGCNA) from 441 adult subjects with a past or current diagnosis of Major Depressive Disorder. After filtering, 5778 genes were clustered in 19 modules. Overall, modules had weak clinical correlation; one module containing 63 genes showed the best correlation with scores on the 9-item Public–Health Questionnaire (PHQ-9) (r = 0.1, p = 0.03). This module was significantly enriched for the Gene Ontology Biological Process Type I Interferon Signaling (adjusted p? 0.001) and other pathways of