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72. Social stress enhances immature neutrophil release from bone marrow in murine Aspergillus fumigatus-induced allergic airway inflammation
Abstracts from the 21st Annual PNIRS Meeting 40 (2014) e1–e52
0, 4 and 24. We used M.I.N.I. International Neuropsychiatric Interview to follow depression and analysed mRNA levels of selected eCB related genes using AffymetrixÒ Human Gene 1.1ST Array. NAPE-PLD and DAGL-a – coding for enzymes involved in eCB synthesis – were lower at baseline in those who developed depression vs those who did not ( 17%, p = 0.02; 17%, p = 0.003; respectively). After 4 weeks, levels of CNR2 – coding for eCB CB2 receptors – were reduced ( 21%, p < 0.001), while levels of FAAH2 – coding for a degrading eCB enzyme – and DAGL-a were increased in the whole sample (+19%, p = 0.01, +19%, p < 0.001, respectively). After controlling for depression development, FAAH2 levels were significantly increased in depressed patients only (+25%, p = 0.005). From baseline to week 24, CNR2 levels decreased in non-depressed patients ( 29%, p < 0.001). Interestingly, at week 24 CNR2 levels were higher in depressed compared with non-depressed individuals (+27%, p = 0.001). Our findings suggest that alterations in the eCB system may underlie the increased vulnerability for depression development in HCV infected patients treated with IFN-a. http://dx.doi.org/10.1016/j.bbi.2014.06.089
70. Sympathetic innervation initiates myeloid cell trafficking from the spleen to the brain that causes the re-establishment of anxiety in stress-sensitized mice D.B. McKim, J.M. Patterson, E.S. Wohleb, B. Jarrett, J.F. Sheridan, J.P. Godbout The Ohio State University, 247 IBMR Building, 460 Medical Center Dr., Columbus, OH 43210, USA Repeated social defeat (RSD) in mice recapitulates key immunological, physiological, and behavioral deficits associated with psychosocial stress in humans. We have reported that exposure to sub-threshold stress 24 days after RSD caused re-establishment of anxiety that was dependent on myeloid cell trafficking from the spleen to the brain. Therefore, we hypothesized that the spleen of RSD-exposed mice becomes a critical reservoir of reactive myeloid cells that are rapidly released following sympathetic activation by sub-threshold stressors. In the first experiments, the spleen was removed before 6 cycles of RSD yet this did not alter initial stressinduced myeloid redistribution or anxiety. Splenectomy prior to RSD, however, prevented the re-distribution of myeloid cells and re-establishment of anxiety following sub-threshold stress 24 days after RSD. Thus, the spleen did not contribute to myeloid cell trafficking and anxiety immediately following RSD, but rather served as a reservoir of myeloid cells that are readily released following sub-threshold stress. To address how these cells are released from the spleen, control and RSD-sensitized mice were treated with guanethidine, a peripheral sympathetic inhibitor, 24 days after RSD prior to sub-threshold stress. Intervention with guanethidine, prior to sub-threshold stress blocked myeloid cell redistribution and anxiety in RSD-sensitized mice. Thus, sympathetic initiation of spleento-brain myeloid cell trafficking represents a novel mechanism in the context of recurring anxiety disorders. http://dx.doi.org/10.1016/j.bbi.2014.06.090
71. A novel combined psychosocial stress paradigm alters tumor VEGF and circulating exosomes in a spontaneous, metastatic model of breast cancer R.P. Dawes, D.K. Byun, E.B. Brown, K.S. Madden University of Rochester Medical Center, Rochester, NY, USA
e21
Metastatic breast cancer carries significant risk of morbidity and mortality with limited treatment options. Psychosocial stress exposure has been linked to tumor growth and metastasis; therefore understanding the underlying neurohormonal mechanisms may yield new therapeutic options and lead to the development of more effective disease interventions. Here we investigated the impact of social isolation combined with acute restraint stress on spontaneous tumor development in MMTV-PyMT mice. Mammary tumor progression in this mouse model of metastatic breast cancer mimics that of invasive ductal carcinoma in humans. Female MMTV-PyMT mice were singly housed at 8 weeks of age during the hyperplastic stage of tumor development. Restraint stress was initiated after 2 weeks of isolation. Control mice remained in their home cages throughout the experiment. Twenty-four hours after the final restraint exposure, stressed mice exhibited elevated circulating corticosterone and splenic normetanephrine (a norepinephrine metabolite), which correlated with increased tumor VEGF and decreased splenic neutrophils. There was no difference in total tumor burden at this early carcinoma stage. Circulating CD63+ exosomes, extracellular vesicles that drive cancer pathogenesis, were decreased. These results demonstrate the dual stressor elicited potent hypothalamic pituitary axis (HPA) and sympathetic nervous system (SNS) activation in conjunction with alterations in the premetastatic tumor that may facilitate progression. http://dx.doi.org/10.1016/j.bbi.2014.06.091
72. Social stress enhances immature neutrophil release from bone marrow in murine Aspergillus fumigatus-induced allergic airway inflammation B.F. Reader, P.D. Nicole, T.J. Andrew, A.C. Juan, M.T. Bailey, J.P. Godbout, J.F. Sheridan The Ohio State University College of Medicine, Institute for Behavioral Medicine Research, 460 Medical Center Dr., 202 IBMR Building, Columbus, OH 43210, USA It is well established that stress enhances inflammation and exacerbates symptoms in diseases including asthma. Nonetheless, the mechanisms by which stress influences disease progression are unknown. Clinical cases of ‘‘severe’’ asthma have been associated with increased neutrophil trafficking to the lung and increased insensitivity of immune cells to the anti-inflammatory and apoptotic effects of glucocorticoids. We hypothesize that these symptoms can be exacerbated by stress and are potential mechanisms by which patients can become refractory to standard treatment and present with prolonged or dysregulated inflammation. To address this issue, we used a murine repeated social defeat (RSD) paradigm that models stress-induced exacerbation of inflammation and immune cell glucocorticoid insensitivity. For instance, previous studies in an Aspergillus fumigatus (Af) allergic airway inflammation paradigm indicate that RSD increased trafficking of glucocorticoid insensitive immune cells, increased inflammation, and delayed the resolution of inflammation in the lung. Here, we show that RSD increased production of bone marrow-derived granulocytes and increased neutrophil trafficking to the lung. Several distinct populations of neutrophils were quantified including immature neutrophils (CD16int/CD49d-), which were significantly increased in the circulation and lung of RSD and Af challenged mice. Taken together, our data indicate that the stressinduced neutrophilia in the context of allergic airway inflammation may not simply be a marker of disease, but a major factor contributing to RSD exacerbation of pulmonary inflammation and disease pathogenesis. http://dx.doi.org/10.1016/j.bbi.2014.06.092
0, 4 and 24. We used M.I.N.I. International Neuropsychiatric Interview to follow depression and analysed mRNA levels of selected eCB related genes using AffymetrixÒ Human Gene 1.1ST Array. NAPE-PLD and DAGL-a – coding for enzymes involved in eCB synthesis – were lower at baseline in those who developed depression vs those who did not ( 17%, p = 0.02; 17%, p = 0.003; respectively). After 4 weeks, levels of CNR2 – coding for eCB CB2 receptors – were reduced ( 21%, p < 0.001), while levels of FAAH2 – coding for a degrading eCB enzyme – and DAGL-a were increased in the whole sample (+19%, p = 0.01, +19%, p < 0.001, respectively). After controlling for depression development, FAAH2 levels were significantly increased in depressed patients only (+25%, p = 0.005). From baseline to week 24, CNR2 levels decreased in non-depressed patients ( 29%, p < 0.001). Interestingly, at week 24 CNR2 levels were higher in depressed compared with non-depressed individuals (+27%, p = 0.001). Our findings suggest that alterations in the eCB system may underlie the increased vulnerability for depression development in HCV infected patients treated with IFN-a. http://dx.doi.org/10.1016/j.bbi.2014.06.089
70. Sympathetic innervation initiates myeloid cell trafficking from the spleen to the brain that causes the re-establishment of anxiety in stress-sensitized mice D.B. McKim, J.M. Patterson, E.S. Wohleb, B. Jarrett, J.F. Sheridan, J.P. Godbout The Ohio State University, 247 IBMR Building, 460 Medical Center Dr., Columbus, OH 43210, USA Repeated social defeat (RSD) in mice recapitulates key immunological, physiological, and behavioral deficits associated with psychosocial stress in humans. We have reported that exposure to sub-threshold stress 24 days after RSD caused re-establishment of anxiety that was dependent on myeloid cell trafficking from the spleen to the brain. Therefore, we hypothesized that the spleen of RSD-exposed mice becomes a critical reservoir of reactive myeloid cells that are rapidly released following sympathetic activation by sub-threshold stressors. In the first experiments, the spleen was removed before 6 cycles of RSD yet this did not alter initial stressinduced myeloid redistribution or anxiety. Splenectomy prior to RSD, however, prevented the re-distribution of myeloid cells and re-establishment of anxiety following sub-threshold stress 24 days after RSD. Thus, the spleen did not contribute to myeloid cell trafficking and anxiety immediately following RSD, but rather served as a reservoir of myeloid cells that are readily released following sub-threshold stress. To address how these cells are released from the spleen, control and RSD-sensitized mice were treated with guanethidine, a peripheral sympathetic inhibitor, 24 days after RSD prior to sub-threshold stress. Intervention with guanethidine, prior to sub-threshold stress blocked myeloid cell redistribution and anxiety in RSD-sensitized mice. Thus, sympathetic initiation of spleento-brain myeloid cell trafficking represents a novel mechanism in the context of recurring anxiety disorders. http://dx.doi.org/10.1016/j.bbi.2014.06.090
71. A novel combined psychosocial stress paradigm alters tumor VEGF and circulating exosomes in a spontaneous, metastatic model of breast cancer R.P. Dawes, D.K. Byun, E.B. Brown, K.S. Madden University of Rochester Medical Center, Rochester, NY, USA
e21
Metastatic breast cancer carries significant risk of morbidity and mortality with limited treatment options. Psychosocial stress exposure has been linked to tumor growth and metastasis; therefore understanding the underlying neurohormonal mechanisms may yield new therapeutic options and lead to the development of more effective disease interventions. Here we investigated the impact of social isolation combined with acute restraint stress on spontaneous tumor development in MMTV-PyMT mice. Mammary tumor progression in this mouse model of metastatic breast cancer mimics that of invasive ductal carcinoma in humans. Female MMTV-PyMT mice were singly housed at 8 weeks of age during the hyperplastic stage of tumor development. Restraint stress was initiated after 2 weeks of isolation. Control mice remained in their home cages throughout the experiment. Twenty-four hours after the final restraint exposure, stressed mice exhibited elevated circulating corticosterone and splenic normetanephrine (a norepinephrine metabolite), which correlated with increased tumor VEGF and decreased splenic neutrophils. There was no difference in total tumor burden at this early carcinoma stage. Circulating CD63+ exosomes, extracellular vesicles that drive cancer pathogenesis, were decreased. These results demonstrate the dual stressor elicited potent hypothalamic pituitary axis (HPA) and sympathetic nervous system (SNS) activation in conjunction with alterations in the premetastatic tumor that may facilitate progression. http://dx.doi.org/10.1016/j.bbi.2014.06.091
72. Social stress enhances immature neutrophil release from bone marrow in murine Aspergillus fumigatus-induced allergic airway inflammation B.F. Reader, P.D. Nicole, T.J. Andrew, A.C. Juan, M.T. Bailey, J.P. Godbout, J.F. Sheridan The Ohio State University College of Medicine, Institute for Behavioral Medicine Research, 460 Medical Center Dr., 202 IBMR Building, Columbus, OH 43210, USA It is well established that stress enhances inflammation and exacerbates symptoms in diseases including asthma. Nonetheless, the mechanisms by which stress influences disease progression are unknown. Clinical cases of ‘‘severe’’ asthma have been associated with increased neutrophil trafficking to the lung and increased insensitivity of immune cells to the anti-inflammatory and apoptotic effects of glucocorticoids. We hypothesize that these symptoms can be exacerbated by stress and are potential mechanisms by which patients can become refractory to standard treatment and present with prolonged or dysregulated inflammation. To address this issue, we used a murine repeated social defeat (RSD) paradigm that models stress-induced exacerbation of inflammation and immune cell glucocorticoid insensitivity. For instance, previous studies in an Aspergillus fumigatus (Af) allergic airway inflammation paradigm indicate that RSD increased trafficking of glucocorticoid insensitive immune cells, increased inflammation, and delayed the resolution of inflammation in the lung. Here, we show that RSD increased production of bone marrow-derived granulocytes and increased neutrophil trafficking to the lung. Several distinct populations of neutrophils were quantified including immature neutrophils (CD16int/CD49d-), which were significantly increased in the circulation and lung of RSD and Af challenged mice. Taken together, our data indicate that the stressinduced neutrophilia in the context of allergic airway inflammation may not simply be a marker of disease, but a major factor contributing to RSD exacerbation of pulmonary inflammation and disease pathogenesis. http://dx.doi.org/10.1016/j.bbi.2014.06.092