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macrophages promote resolution of acute inflammatory pain via an IL-10 dependent pathway
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Abstracts / Brain, Behavior, and Immunity 32 (2013) e1–e47
induced using the well-established ovalbumin model of asthma. Results showed that cohabitation with sick cage mate produced a significant increase in the cellularity of bronchoalveolar lavage fluid (BAL) and cytokines IL-4, IL-5 on BAL supernatant and decrease IL-10 and immunoglobulin IgG2a. However, no significant differences were found in corticosterone levels, IL-13 on BAL, cellularity of bone marrow and peripheral blood. The present data provide experimental evidence that cohabitation with a tumor bearing mice regulate parameters of allergic lung inflammation. FAPESP: 2012/03372–3; 2009/51886–3. http://dx.doi.org/10.1016/j.bbi.2013.07.072
61. Peripheral monocytes/macrophages promote resolution of acute inflammatory pain via an IL-10 dependent pathway H.L. Willemen a, N. Eijkelkamp a, A. Garza Carbajal a, H. Wang a, M. Mack b, J. ZIjlstra a, C.J. Heijnen a,c, A. Kavelaars c a
University Medical Center Utrecht, Laboratory Neuroimmunology and Developmental Origins of Disease, Utrecht, USA b Univesrity Hospital Regensburg, Regensburg, Germany c Laboratory Neuroimmunology of Cancer Related Symptoms (NICRS), Dept. Symptom Research, M.D. Anderson Cancer Center, Houston, TX, USA Chronic pain is a major clinical problem, and understanding mechanisms underlying the transition from acute to chronic pain is needed. We investigated the contribution of peripheral monocytes/macrophages to the transition from acute to persistent IL1beta induced hyperalgesia. As a model, we used LysM-GRK2+/ mice that develop prolonged hyperalgesia in response to IL-1b due to a cell specific reduction in G protein-coupled receptor kinase 2 (GRK2) in lysozyme M-positive microglia/macrophages. In wild type (WT) mice, peripheral monocyte/macrophage depletion prolonged intraplantar IL-1b -induced hyperalgesia from <24 h to >8 days. In LysM-GRK2+/ mice that develop persistent IL-1b hyperalgesia, monocyte/macrophage depletion did not have any effect. Adoptive transfer of WT bone marrow derived monocytes (BMDM), but not of GRK2+/ BMDM, to LysM-GRK2+/ mice prevented the transition to persistent IL-1b-induced hyperalgesia. In search for the mechanism, we show that GRK2-deficient macrophages produce less IL10 in vitro and intrathecal IL-10 adminisration attenuated IL-1binduced hyperalgesia in LysM-GRK2+/ mice. Moreover, in WT mice intrathecal anti-IL10 prolonged IL-1b-induced hyperalgesia. Finally, adoptive transfer of IL-10 / BMDM did not normalize the IL-1binduced hyperalgesia in LysM-GRK2+/ mice. In conclusion, we uncovered a key role for peripheral monocytes/macrophages in promoting resolution of inflammatory hyperalgesia via a mechanism dependent of IL10 signaling. The decreased capacity of GRK2-deficient monocytes/macrophages to produce IL-10 underlies their inability to promote resolution of inflammatory pain. Supported by NIH grants NS073939 and NS074999. http://dx.doi.org/10.1016/j.bbi.2013.07.073
62. Cancer impairs dermal wound healing in mice L.M. Pyter, H. Calero, P.T. Marucha, C.G. Engeland University of Illinois at Chicago, Center for Wound Healing and Tissue Reparation, 801 S. Paulina, Chicago, IL 60612, USA The success of cancer treatment is dependent upon tissue repair (e.g., following surgery, radiation), which if disrupted, can result in treatment delays and dangerous comorbidities. Scant data exist on
tissue repair during cancer. Many cancers suppress the function and quantity of immune cells that are integral to wound healing (e.g., neutrophils, macrophages, T-cells) both locally and in the circulation. We hypothesized that cancer impairs dermal healing and does so through immune cell dysregulation. Oral cancer cells (106) or PBS were injected (s.c.) into the flank of adult female immunocompetent mice. Sixteen days post-tumor induction, two 3.5 mm excisional wounds were placed through the dorsal skin; other mice remained unwounded. Wound tissues or unwounded skin, blood, and tumors were collected 1 or 5 days later. Tumors significantly impaired wound closure by 20–40%. Tumors reduced gene expression of inflammatory factors (IL-10, TLR4, CCL2) in wounds, and increased such factors (CCL3, CCL22, CXCL2, CXCL10) in unwounded skin. The presence of a wound, in turn, reduced IL-6, TNFalpha, and CCL22 gene expression in the tumors themselves. Tumors and wounding, both independently and interactively, also changed the numbers of circulating leukocytes. These data indicate that tumors affect systemic and healthy and damaged skin immunity, and conversely, are immunologically altered themselves by the presence of a wound. This work aims to identify immunological targets by which to promote successful cancer treatment. http://dx.doi.org/10.1016/j.bbi.2013.07.074
63. Heat stress impairs performance parameters, immunity and increases Salmonella enteritidis migration to spleen of broilers chickens J. Palermo-Neto a, A.S. Calefi a, T.P. Aloia a, A.V. Gomes a, M.L. Pinheiro a, A. Ribeiro b, V. Ferraz-de-Paula c, C.S. Astolfi-Ferreira a, A.J. Ferreira a, S. Sharif d, W.M. Quinteiro-Filho a a
University of São Paulo – FMVZ, São Paulo, São Paulo, Brazil Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova, Italy c University of São Paulo, School of Pharmaceutical Sciences, Laboratory of Experimental Toxicology, Brazil d Department of Pathobiology, University of Guelph, Guelph, ON, Canada b
Stressful stimuli are known to change the immune function. A relevant environmental stress to the poultry production is the heat stress. Salmonella spp. is one of the most important zoonotic pathogens worldwide. The aim of our work was search for effects of heat stress on broilers chickens infected with Salmonella enteritidis (SE), searching for a neuroimmune relationship. Two hundred and sixty chickens were divided in four groups:control (C); heat stress (HS); salmonella + control (PC); and salmonella + heat stress (PHS). The chickens were infected or not with Salmonella enteritidis (106 UFC/ animal). Both HS and PHS groups were exposed to 31 ± 1 °C (10 h/ day) from day 35 to 42. At the end of stress (42nd day), we observed that heat stress decreased performance parameters such as body weight (p < 0.01), food intake (p;< 0.01) and food conversion (P < 0.05); increased corticosterone serum levels (p < 0.05); and decreased IgA serum levels, IL-6, IL-12, IL-1b, IL-10, TGF-b, AvBD4, AvBD6 and TLR-2 expression in chickens infected with SE. Heat stress also induced moderate enteritis in chickens of PHS group; additionally, heat stress increased bacterial migration to the spleen (p < 0.05), showing a deficiency of the host to cope with the infection. Thus, we believe that heat stress induced CNS activation increasing corticosterone levels, which in turn decreased the immune system activity and lead to impairment of mucosal barrier, which in turn increased chicken’s susceptibility to Salmonella migration to the spleen. http://dx.doi.org/10.1016/j.bbi.2013.07.075
Abstracts / Brain, Behavior, and Immunity 32 (2013) e1–e47
induced using the well-established ovalbumin model of asthma. Results showed that cohabitation with sick cage mate produced a significant increase in the cellularity of bronchoalveolar lavage fluid (BAL) and cytokines IL-4, IL-5 on BAL supernatant and decrease IL-10 and immunoglobulin IgG2a. However, no significant differences were found in corticosterone levels, IL-13 on BAL, cellularity of bone marrow and peripheral blood. The present data provide experimental evidence that cohabitation with a tumor bearing mice regulate parameters of allergic lung inflammation. FAPESP: 2012/03372–3; 2009/51886–3. http://dx.doi.org/10.1016/j.bbi.2013.07.072
61. Peripheral monocytes/macrophages promote resolution of acute inflammatory pain via an IL-10 dependent pathway H.L. Willemen a, N. Eijkelkamp a, A. Garza Carbajal a, H. Wang a, M. Mack b, J. ZIjlstra a, C.J. Heijnen a,c, A. Kavelaars c a
University Medical Center Utrecht, Laboratory Neuroimmunology and Developmental Origins of Disease, Utrecht, USA b Univesrity Hospital Regensburg, Regensburg, Germany c Laboratory Neuroimmunology of Cancer Related Symptoms (NICRS), Dept. Symptom Research, M.D. Anderson Cancer Center, Houston, TX, USA Chronic pain is a major clinical problem, and understanding mechanisms underlying the transition from acute to chronic pain is needed. We investigated the contribution of peripheral monocytes/macrophages to the transition from acute to persistent IL1beta induced hyperalgesia. As a model, we used LysM-GRK2+/ mice that develop prolonged hyperalgesia in response to IL-1b due to a cell specific reduction in G protein-coupled receptor kinase 2 (GRK2) in lysozyme M-positive microglia/macrophages. In wild type (WT) mice, peripheral monocyte/macrophage depletion prolonged intraplantar IL-1b -induced hyperalgesia from <24 h to >8 days. In LysM-GRK2+/ mice that develop persistent IL-1b hyperalgesia, monocyte/macrophage depletion did not have any effect. Adoptive transfer of WT bone marrow derived monocytes (BMDM), but not of GRK2+/ BMDM, to LysM-GRK2+/ mice prevented the transition to persistent IL-1b-induced hyperalgesia. In search for the mechanism, we show that GRK2-deficient macrophages produce less IL10 in vitro and intrathecal IL-10 adminisration attenuated IL-1binduced hyperalgesia in LysM-GRK2+/ mice. Moreover, in WT mice intrathecal anti-IL10 prolonged IL-1b-induced hyperalgesia. Finally, adoptive transfer of IL-10 / BMDM did not normalize the IL-1binduced hyperalgesia in LysM-GRK2+/ mice. In conclusion, we uncovered a key role for peripheral monocytes/macrophages in promoting resolution of inflammatory hyperalgesia via a mechanism dependent of IL10 signaling. The decreased capacity of GRK2-deficient monocytes/macrophages to produce IL-10 underlies their inability to promote resolution of inflammatory pain. Supported by NIH grants NS073939 and NS074999. http://dx.doi.org/10.1016/j.bbi.2013.07.073
62. Cancer impairs dermal wound healing in mice L.M. Pyter, H. Calero, P.T. Marucha, C.G. Engeland University of Illinois at Chicago, Center for Wound Healing and Tissue Reparation, 801 S. Paulina, Chicago, IL 60612, USA The success of cancer treatment is dependent upon tissue repair (e.g., following surgery, radiation), which if disrupted, can result in treatment delays and dangerous comorbidities. Scant data exist on
tissue repair during cancer. Many cancers suppress the function and quantity of immune cells that are integral to wound healing (e.g., neutrophils, macrophages, T-cells) both locally and in the circulation. We hypothesized that cancer impairs dermal healing and does so through immune cell dysregulation. Oral cancer cells (106) or PBS were injected (s.c.) into the flank of adult female immunocompetent mice. Sixteen days post-tumor induction, two 3.5 mm excisional wounds were placed through the dorsal skin; other mice remained unwounded. Wound tissues or unwounded skin, blood, and tumors were collected 1 or 5 days later. Tumors significantly impaired wound closure by 20–40%. Tumors reduced gene expression of inflammatory factors (IL-10, TLR4, CCL2) in wounds, and increased such factors (CCL3, CCL22, CXCL2, CXCL10) in unwounded skin. The presence of a wound, in turn, reduced IL-6, TNFalpha, and CCL22 gene expression in the tumors themselves. Tumors and wounding, both independently and interactively, also changed the numbers of circulating leukocytes. These data indicate that tumors affect systemic and healthy and damaged skin immunity, and conversely, are immunologically altered themselves by the presence of a wound. This work aims to identify immunological targets by which to promote successful cancer treatment. http://dx.doi.org/10.1016/j.bbi.2013.07.074
63. Heat stress impairs performance parameters, immunity and increases Salmonella enteritidis migration to spleen of broilers chickens J. Palermo-Neto a, A.S. Calefi a, T.P. Aloia a, A.V. Gomes a, M.L. Pinheiro a, A. Ribeiro b, V. Ferraz-de-Paula c, C.S. Astolfi-Ferreira a, A.J. Ferreira a, S. Sharif d, W.M. Quinteiro-Filho a a
University of São Paulo – FMVZ, São Paulo, São Paulo, Brazil Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova, Italy c University of São Paulo, School of Pharmaceutical Sciences, Laboratory of Experimental Toxicology, Brazil d Department of Pathobiology, University of Guelph, Guelph, ON, Canada b
Stressful stimuli are known to change the immune function. A relevant environmental stress to the poultry production is the heat stress. Salmonella spp. is one of the most important zoonotic pathogens worldwide. The aim of our work was search for effects of heat stress on broilers chickens infected with Salmonella enteritidis (SE), searching for a neuroimmune relationship. Two hundred and sixty chickens were divided in four groups:control (C); heat stress (HS); salmonella + control (PC); and salmonella + heat stress (PHS). The chickens were infected or not with Salmonella enteritidis (106 UFC/ animal). Both HS and PHS groups were exposed to 31 ± 1 °C (10 h/ day) from day 35 to 42. At the end of stress (42nd day), we observed that heat stress decreased performance parameters such as body weight (p < 0.01), food intake (p;< 0.01) and food conversion (P < 0.05); increased corticosterone serum levels (p < 0.05); and decreased IgA serum levels, IL-6, IL-12, IL-1b, IL-10, TGF-b, AvBD4, AvBD6 and TLR-2 expression in chickens infected with SE. Heat stress also induced moderate enteritis in chickens of PHS group; additionally, heat stress increased bacterial migration to the spleen (p < 0.05), showing a deficiency of the host to cope with the infection. Thus, we believe that heat stress induced CNS activation increasing corticosterone levels, which in turn decreased the immune system activity and lead to impairment of mucosal barrier, which in turn increased chicken’s susceptibility to Salmonella migration to the spleen. http://dx.doi.org/10.1016/j.bbi.2013.07.075