- Email: [email protected]
Abstract # 3176 Systemic lipopolysaccharide (LPS) prevents microglial loss after CSF1 receptor blockade
e36
Abstracts / Brain, Behavior, and Immunity 76 (2019) e1–e43
Abstract # 3175 Mycobacterium vaccae immunization protects aged rats from surgery-elicited neuroinflammation and cognitive dysfunction L.K. Fonken a,b, M.G. Frank b, H.M. D’Angelo b, L.R. Watkins b, C.A. Lowry b, S.F. Maier b a University of Texas at Austin, Division of Pharmacology and Toxicology, 107 W. Dean Keeton, BME 3.510C, Austin, TX 78712, United States b University of Colorado Boulder, United States
Advanced age is a major risk factor for developing postoperative cognitive dysfunction (POCD). Age-related neuroinflammatory ‘‘priming” may contribute to POCD: peripheral immune stimuli (e. g., infection or surgery) cause exaggerated pro-inflammatory responses in the aged brain that can elicit pathology. Exposure to micro-organisms with immunoregulatory and anti-inflammatory properties may be a promising strategy to quell neuroinflammatory priming. We hypothesized that immunization with Mycobacterium vaccae (M. vaccae; NCTC11659) would reduce neuroinflammation and cognitive impairments in aged rats post-surgery. Aged (24mos) and adult (3mos) male F344XBN rats received subcutaneous injections of heat-killed M. vaccae (3 injections, once per week) and then 5 days following the final M. vaccae injection rats underwent a laparotomy or sham (anesthesia control) procedure. Three days post-surgery, rats were trained in a fear conditioning paradigm or tissue was collected. Aged (but not young) rats showed post-operative memory deficits. Prophylactic treatment with M. vaccae protected aged rats from surgery induced-cognitive impairments. Furthermore, M. vaccae treatment shifted the aged proinflammatory hippocampal microenvironment (increased IL-1beta and NFKBIA) towards an anti-inflammatory phenotype (increased IL-4 and Arg1). Microglia may mediate the anti-inflammatory effects of M. vaccae in the brain: prior in vivo treatment with M. vaccae reduced hyperinflammatory responses to ex vivo lipopolysaccharide in microglia isolated from aged rats. Overall, our novel data suggest that M. vaccae can re-direct a primed neuroimmune environment in aged rats and prevent POCD. http://dx.doi.org/10.1016/j.bbi.2018.11.286
Abstract # 3176 Systemic lipopolysaccharide (LPS) prevents microglial loss after CSF1 receptor blockade J.S. Grigoleit, W.A. Eckert III, L. Fourgeaud, Y. He, A. Bhattacharya Janssen Research & Development, LLC, Neuroscience, 3210 Merryfield Row, La Jolla, CA 92121, United States Drug-induced colony-stimulating factor 1 receptor (CSF1R) blockage is now a commonly used tool to cause reversible microglia depletion in mice. However, microglial depletion is not complete with a remaining fraction of approximately 5% of the original microglia. In order to characterize this remarkably stable portion of the microglia we used fluorescent cytometry (FACS) and mass cytometry (CyTOF) in PLX3397-treated mice and found that the microglia in those animals represents a unique population different from normal microglia and bearing a lot of features usually associated with a proinflammatory and activated phenotype. In addition, behavioral analyses revealed subtle changes that may be interpreted as sickness behavior. Treated with a peripheral injection of LPS, (0.8 mg/kg ip) remaining microglia of depleted animals showed a much stronger inflammatory response and such-treated animals displayed a more pronounced behavioral response to LPS than control animals. Finally, we injected animals that were just at the beginning of their 1 week PLX3397 treatment with LPS and surprisingly found the resulting neuroinflammatory response to be capable of blocking
the PLX-induced microglia depletion and inducing a microglial phenotype that was different from control, only LPS-treated and only PLX-treated microglia. Our observation is consistent with the emerging science that microglia do have different roles and phenotypes depending on cellular environment and disease pathology and remains to be studied in greater detail. http://dx.doi.org/10.1016/j.bbi.2018.11.287
Abstract # 3177 Early infant institutionalization leads to a premature accumulation of terminally differentiated CD57 + T cells by adolescence C.L. Coe, B. Donzella, D. Sheerar, M. Gunnar University of Minnesota, 22 N Charter Street, Madison, WI 53715, United States Early rearing conditions can exert a strong influence on the immune system, affecting regulation and the capacity to respond effectively to pathogens. Most PNI research focuses on inflammatory processes, but the absence of typical parenting can also result in a polarization of T cells. An optimized multicolor immunophenotyping panel was used to enumerate T cell lineages, comparing adolescents who had spent 1–2 years in an orphanage to typically raised teenagers. This presentation will focus primarily on CD4 + CD57 + and CD8 + CD57 + cells, further subdivided into naïve, central memory and effector/memory subsets, including cells in the terminally differentiated state. As compared to family-reared American teenagers, the adopted adolescents, especially males, had significantly more TEMRA cells. High frequencies of this cell population are normally associated with aging and immune senescence in older adults, resulting in a lower homeostatic capacity. They also reflect sustained activation and participate in containing latent Herpes viruses. Institutional rearing during infancy was associated with a greater likelihood of being CMV seropositive, which contributed to, but did not entirely account for the persistent effects of early rearing on T cell profiles in male adolescents. Our analysis also found that rearing conditions affected cytokine responses to several T cell and inflammatory stimulants in culture. Following overnight stimulation of whole blood with PHA, LPS, IO/PMA, or anti-CD3/anti-CD28 MoAB, cytokine concentrations were determined by multi-analyte electrochemiluminesence array. http://dx.doi.org/10.1016/j.bbi.2018.11.288
Abstract # 3178 Maternal viral infection causes global changes in fetal microglia and alters gene expression and microglia density in the fetal amygdala A.M. Antonson, R.W. Johnson University of Illinois Urbana-Champaign, 1201 W Gregory Dr, Edward R. Madigan Laboratory, Rm 250, Urbana, IL 61801, United States Prenatal exposure to maternal infection increases the risk of neurodevelopmental disorders, though the mechanisms remain to be elucidated. We have previously established a maternal immune activation (MIA) swine model, which results in altered piglet social behaviors postnatally, without microglia activation. Here, we sought to identify microglia activity prenatally, immediately following maternal infection with live porcine reproductive and respiratory syndrome virus (PRRSV). Cesarean sections performed 7 and 21 days post-inoculation (dpi) revealed that MIA fetuses had reduced brain weights and that MIA microglia expressed more of the classical
Abstracts / Brain, Behavior, and Immunity 76 (2019) e1–e43
Abstract # 3175 Mycobacterium vaccae immunization protects aged rats from surgery-elicited neuroinflammation and cognitive dysfunction L.K. Fonken a,b, M.G. Frank b, H.M. D’Angelo b, L.R. Watkins b, C.A. Lowry b, S.F. Maier b a University of Texas at Austin, Division of Pharmacology and Toxicology, 107 W. Dean Keeton, BME 3.510C, Austin, TX 78712, United States b University of Colorado Boulder, United States
Advanced age is a major risk factor for developing postoperative cognitive dysfunction (POCD). Age-related neuroinflammatory ‘‘priming” may contribute to POCD: peripheral immune stimuli (e. g., infection or surgery) cause exaggerated pro-inflammatory responses in the aged brain that can elicit pathology. Exposure to micro-organisms with immunoregulatory and anti-inflammatory properties may be a promising strategy to quell neuroinflammatory priming. We hypothesized that immunization with Mycobacterium vaccae (M. vaccae; NCTC11659) would reduce neuroinflammation and cognitive impairments in aged rats post-surgery. Aged (24mos) and adult (3mos) male F344XBN rats received subcutaneous injections of heat-killed M. vaccae (3 injections, once per week) and then 5 days following the final M. vaccae injection rats underwent a laparotomy or sham (anesthesia control) procedure. Three days post-surgery, rats were trained in a fear conditioning paradigm or tissue was collected. Aged (but not young) rats showed post-operative memory deficits. Prophylactic treatment with M. vaccae protected aged rats from surgery induced-cognitive impairments. Furthermore, M. vaccae treatment shifted the aged proinflammatory hippocampal microenvironment (increased IL-1beta and NFKBIA) towards an anti-inflammatory phenotype (increased IL-4 and Arg1). Microglia may mediate the anti-inflammatory effects of M. vaccae in the brain: prior in vivo treatment with M. vaccae reduced hyperinflammatory responses to ex vivo lipopolysaccharide in microglia isolated from aged rats. Overall, our novel data suggest that M. vaccae can re-direct a primed neuroimmune environment in aged rats and prevent POCD. http://dx.doi.org/10.1016/j.bbi.2018.11.286
Abstract # 3176 Systemic lipopolysaccharide (LPS) prevents microglial loss after CSF1 receptor blockade J.S. Grigoleit, W.A. Eckert III, L. Fourgeaud, Y. He, A. Bhattacharya Janssen Research & Development, LLC, Neuroscience, 3210 Merryfield Row, La Jolla, CA 92121, United States Drug-induced colony-stimulating factor 1 receptor (CSF1R) blockage is now a commonly used tool to cause reversible microglia depletion in mice. However, microglial depletion is not complete with a remaining fraction of approximately 5% of the original microglia. In order to characterize this remarkably stable portion of the microglia we used fluorescent cytometry (FACS) and mass cytometry (CyTOF) in PLX3397-treated mice and found that the microglia in those animals represents a unique population different from normal microglia and bearing a lot of features usually associated with a proinflammatory and activated phenotype. In addition, behavioral analyses revealed subtle changes that may be interpreted as sickness behavior. Treated with a peripheral injection of LPS, (0.8 mg/kg ip) remaining microglia of depleted animals showed a much stronger inflammatory response and such-treated animals displayed a more pronounced behavioral response to LPS than control animals. Finally, we injected animals that were just at the beginning of their 1 week PLX3397 treatment with LPS and surprisingly found the resulting neuroinflammatory response to be capable of blocking
the PLX-induced microglia depletion and inducing a microglial phenotype that was different from control, only LPS-treated and only PLX-treated microglia. Our observation is consistent with the emerging science that microglia do have different roles and phenotypes depending on cellular environment and disease pathology and remains to be studied in greater detail. http://dx.doi.org/10.1016/j.bbi.2018.11.287
Abstract # 3177 Early infant institutionalization leads to a premature accumulation of terminally differentiated CD57 + T cells by adolescence C.L. Coe, B. Donzella, D. Sheerar, M. Gunnar University of Minnesota, 22 N Charter Street, Madison, WI 53715, United States Early rearing conditions can exert a strong influence on the immune system, affecting regulation and the capacity to respond effectively to pathogens. Most PNI research focuses on inflammatory processes, but the absence of typical parenting can also result in a polarization of T cells. An optimized multicolor immunophenotyping panel was used to enumerate T cell lineages, comparing adolescents who had spent 1–2 years in an orphanage to typically raised teenagers. This presentation will focus primarily on CD4 + CD57 + and CD8 + CD57 + cells, further subdivided into naïve, central memory and effector/memory subsets, including cells in the terminally differentiated state. As compared to family-reared American teenagers, the adopted adolescents, especially males, had significantly more TEMRA cells. High frequencies of this cell population are normally associated with aging and immune senescence in older adults, resulting in a lower homeostatic capacity. They also reflect sustained activation and participate in containing latent Herpes viruses. Institutional rearing during infancy was associated with a greater likelihood of being CMV seropositive, which contributed to, but did not entirely account for the persistent effects of early rearing on T cell profiles in male adolescents. Our analysis also found that rearing conditions affected cytokine responses to several T cell and inflammatory stimulants in culture. Following overnight stimulation of whole blood with PHA, LPS, IO/PMA, or anti-CD3/anti-CD28 MoAB, cytokine concentrations were determined by multi-analyte electrochemiluminesence array. http://dx.doi.org/10.1016/j.bbi.2018.11.288
Abstract # 3178 Maternal viral infection causes global changes in fetal microglia and alters gene expression and microglia density in the fetal amygdala A.M. Antonson, R.W. Johnson University of Illinois Urbana-Champaign, 1201 W Gregory Dr, Edward R. Madigan Laboratory, Rm 250, Urbana, IL 61801, United States Prenatal exposure to maternal infection increases the risk of neurodevelopmental disorders, though the mechanisms remain to be elucidated. We have previously established a maternal immune activation (MIA) swine model, which results in altered piglet social behaviors postnatally, without microglia activation. Here, we sought to identify microglia activity prenatally, immediately following maternal infection with live porcine reproductive and respiratory syndrome virus (PRRSV). Cesarean sections performed 7 and 21 days post-inoculation (dpi) revealed that MIA fetuses had reduced brain weights and that MIA microglia expressed more of the classical