TY  - JOUR
AU  - Petrušić, Marija
AU  - Stojić-Vukanić, Zorica
AU  - Pilipović, Ivan
AU  - Kosec, Duško
AU  - Prijić, Ivana
AU  - Leposavić, Gordana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4316
AB  - The study was aimed to examine putative contribution of thymic involution to ageing-associated increase in susceptibility of Albino Oxford (AO) rats to the development of clinical EAE, and vice versa influence of the disease on the progression of thymic involution. To this end we examined (i) the parameters of thymocyte negative selection efficacy, the thymic generation of CD4+CD25+Foxp3+ T regulatory cells (Tregs) and thymic capacity to instruct/predetermine IL-17-producing T-cell differentiation, and thymopietic efficacy-associated accumulation of “inflammescent” cytotoxic CD28- T cells in the periphery, and (ii) the key underlying mechanisms in young and old non-immunised AO rats and their counterparts immunised for EAE (on the 16th day post-immunisation when the disease in old rats reached the plateau) using flow cytometry analysis and/or RT-qPCR. It was found that thymic involution impairs: (i) the efficacy of negative selection (by affecting thymocyte expression of CD90, negative regulator of selection threshold and the expression of thymic stromal cell integrity factors) and (ii) Treg generation (by diminishing expression of cytokines supporting their differentiation/maturation). Additionally, the results suggest that thymic involution facilitates CD8+ T-cell differentiation into IL-17-producing cells (previously linked to the development of clinical EAE in old AO rats). Furthermore, they confirmed that ageing-related decrease in thymic T-cell output (as indicated by diminished frequency of recent thymic emigrants in peripheral blood) resulted in the accumulation of CD28- T cells in peripheral blood and, upon immunisation, in the target organ. On the other hand, the development of EAE (most likely by increasing circulatory levels of proinflammatory cytokines) contributed to the decline in thymic output of T cells, including Tregs, and thereby to the progression/maintenance of clinical EAE. Thus, in AO rats thymic involution via multi-layered mechanisms may favour the development of clinically manifested autoimmunity, which, in turn, precipitates the thymus atrophy.
PB  - Elsevier Inc.
T2  - Experimental Gerontology
T1  - Thymic changes as a contributing factor in the increased susceptibility of old Albino Oxford rats to EAE development
VL  - 171
DO  - 10.1016/j.exger.2022.112009
ER  - 

@article{
author = "Petrušić, Marija and Stojić-Vukanić, Zorica and Pilipović, Ivan and Kosec, Duško and Prijić, Ivana and Leposavić, Gordana",
year = "2023",
abstract = "The study was aimed to examine putative contribution of thymic involution to ageing-associated increase in susceptibility of Albino Oxford (AO) rats to the development of clinical EAE, and vice versa influence of the disease on the progression of thymic involution. To this end we examined (i) the parameters of thymocyte negative selection efficacy, the thymic generation of CD4+CD25+Foxp3+ T regulatory cells (Tregs) and thymic capacity to instruct/predetermine IL-17-producing T-cell differentiation, and thymopietic efficacy-associated accumulation of “inflammescent” cytotoxic CD28- T cells in the periphery, and (ii) the key underlying mechanisms in young and old non-immunised AO rats and their counterparts immunised for EAE (on the 16th day post-immunisation when the disease in old rats reached the plateau) using flow cytometry analysis and/or RT-qPCR. It was found that thymic involution impairs: (i) the efficacy of negative selection (by affecting thymocyte expression of CD90, negative regulator of selection threshold and the expression of thymic stromal cell integrity factors) and (ii) Treg generation (by diminishing expression of cytokines supporting their differentiation/maturation). Additionally, the results suggest that thymic involution facilitates CD8+ T-cell differentiation into IL-17-producing cells (previously linked to the development of clinical EAE in old AO rats). Furthermore, they confirmed that ageing-related decrease in thymic T-cell output (as indicated by diminished frequency of recent thymic emigrants in peripheral blood) resulted in the accumulation of CD28- T cells in peripheral blood and, upon immunisation, in the target organ. On the other hand, the development of EAE (most likely by increasing circulatory levels of proinflammatory cytokines) contributed to the decline in thymic output of T cells, including Tregs, and thereby to the progression/maintenance of clinical EAE. Thus, in AO rats thymic involution via multi-layered mechanisms may favour the development of clinically manifested autoimmunity, which, in turn, precipitates the thymus atrophy.",
publisher = "Elsevier Inc.",
journal = "Experimental Gerontology",
title = "Thymic changes as a contributing factor in the increased susceptibility of old Albino Oxford rats to EAE development",
volume = "171",
doi = "10.1016/j.exger.2022.112009"
}

Petrušić, M., Stojić-Vukanić, Z., Pilipović, I., Kosec, D., Prijić, I.,& Leposavić, G.. (2023). Thymic changes as a contributing factor in the increased susceptibility of old Albino Oxford rats to EAE development. in Experimental Gerontology
Elsevier Inc.., 171.
https://doi.org/10.1016/j.exger.2022.112009

Petrušić M, Stojić-Vukanić Z, Pilipović I, Kosec D, Prijić I, Leposavić G. Thymic changes as a contributing factor in the increased susceptibility of old Albino Oxford rats to EAE development. in Experimental Gerontology. 2023;171.
doi:10.1016/j.exger.2022.112009 .

Petrušić, Marija, Stojić-Vukanić, Zorica, Pilipović, Ivan, Kosec, Duško, Prijić, Ivana, Leposavić, Gordana, "Thymic changes as a contributing factor in the increased susceptibility of old Albino Oxford rats to EAE development" in Experimental Gerontology, 171 (2023),
https://doi.org/10.1016/j.exger.2022.112009 . .

TY  - JOUR
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Prijić, Ivana
AU  - Jasnić, Nebojša
AU  - Đorđević, Jelena
AU  - Leposavić, Gordana
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4198
AB  - Our previous studies showed more severe experimental autoimmune encephalomyelitis (EAE) in male compared with female adult rats, and moderating effect of propranolol-induced β-adrenoceptor blockade on EAE in females, the effect associated with transcriptional stimulation of Nrf2/HO-1 axis in spinal cord microglia. This study examined putative sexual dimor- phism in propranolol action on EAE severity. Propranolol treatment beginning from the onset of clinical EAE mitigated EAE severity in rats of both sexes, but to a greater extent in males exhibiting higher noradrenaline levels and myeloid cell β 2 -adrenoceptor expression in spinal cord. This correlated with more prominent stimulatory effects of propranolol not only on CX3CL1/CX3CR1/Nrf2/HO-1 cascade, but also on Stat3/Socs3 signaling axis in spinal cord microglia/myeloid cells (mirrored in the decreased Stat3 and the increased Socs3 expression) from male rats compared with their female counterparts. Propranolol diminished the frequency of activated cells among microglia, increased their phagocyting/endocyting capacity, and shifted cytokine secretory profile of microglia/blood-borne myeloid cells towards an anti-inflammatory/neuroprotective phenotype. Additionally, it downregulated the expression of chemokines (CCL2, CCL19/21) driving T-cell/monocyte traf- ficking into spinal cord. Consequently, in propranolol-treated rats fewer activated CD4+ T cells and IL-17+ T cells, including CD4+IL17+ cells coexpressing IFN-γ/GM-CSF, were recovered from spinal cord of propranolol-treated rats compared with sex-matched saline-injected controls. All the effects of propranolol were more prominent in males. The study as a whole disclosed that sexual dimorphism in multiple molecular mechanisms implicated in EAE development may be responsible for greater severity of EAE in male rats and sexually dimorphic action of substances affecting them.
PB  - Springer
T2  - Cellular and Molecular Neurobiology
T1  - β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males
DO  - 10.1007/s10571-022-01246-z
ER  - 

@article{
author = "Pilipović, Ivan and Stojić-Vukanić, Zorica and Prijić, Ivana and Jasnić, Nebojša and Đorđević, Jelena and Leposavić, Gordana",
year = "2022",
abstract = "Our previous studies showed more severe experimental autoimmune encephalomyelitis (EAE) in male compared with female adult rats, and moderating effect of propranolol-induced β-adrenoceptor blockade on EAE in females, the effect associated with transcriptional stimulation of Nrf2/HO-1 axis in spinal cord microglia. This study examined putative sexual dimor- phism in propranolol action on EAE severity. Propranolol treatment beginning from the onset of clinical EAE mitigated EAE severity in rats of both sexes, but to a greater extent in males exhibiting higher noradrenaline levels and myeloid cell β 2 -adrenoceptor expression in spinal cord. This correlated with more prominent stimulatory effects of propranolol not only on CX3CL1/CX3CR1/Nrf2/HO-1 cascade, but also on Stat3/Socs3 signaling axis in spinal cord microglia/myeloid cells (mirrored in the decreased Stat3 and the increased Socs3 expression) from male rats compared with their female counterparts. Propranolol diminished the frequency of activated cells among microglia, increased their phagocyting/endocyting capacity, and shifted cytokine secretory profile of microglia/blood-borne myeloid cells towards an anti-inflammatory/neuroprotective phenotype. Additionally, it downregulated the expression of chemokines (CCL2, CCL19/21) driving T-cell/monocyte traf- ficking into spinal cord. Consequently, in propranolol-treated rats fewer activated CD4+ T cells and IL-17+ T cells, including CD4+IL17+ cells coexpressing IFN-γ/GM-CSF, were recovered from spinal cord of propranolol-treated rats compared with sex-matched saline-injected controls. All the effects of propranolol were more prominent in males. The study as a whole disclosed that sexual dimorphism in multiple molecular mechanisms implicated in EAE development may be responsible for greater severity of EAE in male rats and sexually dimorphic action of substances affecting them.",
publisher = "Springer",
journal = "Cellular and Molecular Neurobiology",
title = "β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males",
doi = "10.1007/s10571-022-01246-z"
}

Pilipović, I., Stojić-Vukanić, Z., Prijić, I., Jasnić, N., Đorđević, J.,& Leposavić, G.. (2022). β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males. in Cellular and Molecular Neurobiology
Springer..
https://doi.org/10.1007/s10571-022-01246-z

Pilipović I, Stojić-Vukanić Z, Prijić I, Jasnić N, Đorđević J, Leposavić G. β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males. in Cellular and Molecular Neurobiology. 2022;.
doi:10.1007/s10571-022-01246-z .

Pilipović, Ivan, Stojić-Vukanić, Zorica, Prijić, Ivana, Jasnić, Nebojša, Đorđević, Jelena, Leposavić, Gordana, "β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males" in Cellular and Molecular Neurobiology (2022),
https://doi.org/10.1007/s10571-022-01246-z . .

TY  - CONF
AU  - Pilipović, Ivan
AU  - Prijić, Ivana
AU  - Stojić-Vukanić, Zorica
AU  - Leposavić, Gordana
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4724
AB  - Our previous studies showed more severe EAE in male compared with female adult rats, and moderating effect of propranolol‐induced β‐adrenoceptor blockade on EAE in female rats through stimulation of Nrf2/HO‐1 signalling pathway in spinal cord microglia. This study was designed to examine putative sexual dimorphism in Nrf2/HO‐1 signalling pathway and CX3CL1, as one of its activators. Propranolol treatment beginning from the appearance of the first clinical signs of EAE mitigated the disease severity in rats of both sexes, but its effect was more prominent in males. This correlated with more prominent effect of propranolol on the expression of CX3CL1 in spinal cord tissue, CX3CR1 on microglial surface, and Nrf2/HO‐1 in spinal cord microglia in males. Consistently, the proportion of CX3CR1‐expressing microglia and CX3CR1 density on their surface increased more prominently in males. 
Consistently, propranolol increased the proportion of IL‐10/TGF‐β‐producing microglia and microglia expressing CD163, molecule highlighting ramified microglia with neuroprotective 
properties in damaged tissue, to a greater extent in males. Additionally, propranolol increased phagocyting capacity of microglia to a greater extent in males. Moreover, propranolol more prominently decreased the frequency of blood‐borne myeloid cells and highly pathogenic IL‐17+ T‐cells, coexpressing GM‐CSF/IFN‐γ, in male rat spinal cord. This correlated with greater reducing effect of propranolol on the spinal cord tissue expression of CCL2/CCL19/CCL21 chemokines in males. The study as a whole indicates that sexual dimorphism in CX3CR1/Nrf2/HO‐1 spinal cord axis could contribute to greater severity of EAE in male rats, and sexually dimorphic action of substances affecting its signalling capacity.
C3  - European Journal of Immunology
T1  - Sexual dimorphism in CX3CR1/Nrf2/HO‐1 spinal cord axis affects therapeutic efficacy of β‐adrenoceptor blockade in EAE rats
VL  - 51
IS  - Suppl.1
SP  - 246
EP  - 246
DO  - 10.1002/eji.202170200
ER  - 

@conference{
author = "Pilipović, Ivan and Prijić, Ivana and Stojić-Vukanić, Zorica and Leposavić, Gordana",
year = "2021",
abstract = "Our previous studies showed more severe EAE in male compared with female adult rats, and moderating effect of propranolol‐induced β‐adrenoceptor blockade on EAE in female rats through stimulation of Nrf2/HO‐1 signalling pathway in spinal cord microglia. This study was designed to examine putative sexual dimorphism in Nrf2/HO‐1 signalling pathway and CX3CL1, as one of its activators. Propranolol treatment beginning from the appearance of the first clinical signs of EAE mitigated the disease severity in rats of both sexes, but its effect was more prominent in males. This correlated with more prominent effect of propranolol on the expression of CX3CL1 in spinal cord tissue, CX3CR1 on microglial surface, and Nrf2/HO‐1 in spinal cord microglia in males. Consistently, the proportion of CX3CR1‐expressing microglia and CX3CR1 density on their surface increased more prominently in males. 
Consistently, propranolol increased the proportion of IL‐10/TGF‐β‐producing microglia and microglia expressing CD163, molecule highlighting ramified microglia with neuroprotective 
properties in damaged tissue, to a greater extent in males. Additionally, propranolol increased phagocyting capacity of microglia to a greater extent in males. Moreover, propranolol more prominently decreased the frequency of blood‐borne myeloid cells and highly pathogenic IL‐17+ T‐cells, coexpressing GM‐CSF/IFN‐γ, in male rat spinal cord. This correlated with greater reducing effect of propranolol on the spinal cord tissue expression of CCL2/CCL19/CCL21 chemokines in males. The study as a whole indicates that sexual dimorphism in CX3CR1/Nrf2/HO‐1 spinal cord axis could contribute to greater severity of EAE in male rats, and sexually dimorphic action of substances affecting its signalling capacity.",
journal = "European Journal of Immunology",
title = "Sexual dimorphism in CX3CR1/Nrf2/HO‐1 spinal cord axis affects therapeutic efficacy of β‐adrenoceptor blockade in EAE rats",
volume = "51",
number = "Suppl.1",
pages = "246-246",
doi = "10.1002/eji.202170200"
}

Pilipović, I., Prijić, I., Stojić-Vukanić, Z.,& Leposavić, G.. (2021). Sexual dimorphism in CX3CR1/Nrf2/HO‐1 spinal cord axis affects therapeutic efficacy of β‐adrenoceptor blockade in EAE rats. in European Journal of Immunology, 51(Suppl.1), 246-246.
https://doi.org/10.1002/eji.202170200

Pilipović I, Prijić I, Stojić-Vukanić Z, Leposavić G. Sexual dimorphism in CX3CR1/Nrf2/HO‐1 spinal cord axis affects therapeutic efficacy of β‐adrenoceptor blockade in EAE rats. in European Journal of Immunology. 2021;51(Suppl.1):246-246.
doi:10.1002/eji.202170200 .

Pilipović, Ivan, Prijić, Ivana, Stojić-Vukanić, Zorica, Leposavić, Gordana, "Sexual dimorphism in CX3CR1/Nrf2/HO‐1 spinal cord axis affects therapeutic efficacy of β‐adrenoceptor blockade in EAE rats" in European Journal of Immunology, 51, no. Suppl.1 (2021):246-246,
https://doi.org/10.1002/eji.202170200 . .

TY  - CONF
AU  - Prijić, Ivana
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Leposavić, Gordana
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5089
AB  - Претпоставља се да дисфункција симпатичког нервног система 
доприноси развоју мултипле склерозе и експерименталног аутоимунског 
енцефаломијелитиса (ЕАЕ). Имајући у виду важност микроглије за 
развој/резолуцију неуроинфламације, испитиван је имуномодулаторни 
потенцијал главног симпатичког медијатора норадреналина коришћењем 
пацовског модела ЕАЕ-а. Резултати су показали да третман пропранололом, 
неселективним блокатором β-адренергичких рецептора, у ефекторској 
фази ЕАЕ-а смањује тежину болести. Ово је корелирало са повећаном 
заступљеношћу микроглије која експримира CX3CR1, кључан молекул за 
њену имуномодулаторну/неуропротективну активност, и њеном појачаном 
експресијом Nrf2 гена, као и гена за хем оксигеназу-1, која се сматра 
ефекторским молекулом анти-инфламаторног CX3CR1/Nrf2 сигналног 
пута. Истраживања in vitro показала су да активација β-адренергичких 
рецептора доводи до нисходне регулације експресије Nrf2 и путем 
независним од CX3CR1. Сходно претходним резултатима, пропранолол 
је повећао фагоцитну способност микроглије, што је корелирало са 
повећањем површинске експресије анти-инфламаторних маркера CD163 
и CD83. Повећање експресије хем оксигеназе-1 праћено је порастом 
заступљености микроглије која синтетише IL-10, а смањењем удела оне 
која експримира проинфламаторне цитокине IL-1β и IL-23. Пропранолол 
је смањио и експресију MCP-1/CCL2 у кичменој мождини. Консекутивно, 
инфилтрација кичмене мождине мијелоидним ћелијама и CD4+ Т-ћелијама 
била је смањена код пацова третираних пропранололом. У складу са свим 
претходним, пропранолол је лимитирао и реактивацију/пролиферацију 
CD4+ Т-лимфоцита и њихову диференцијацију у изузетно патогене IL 17+IFN-γ+GM-CSF+ ћелије. Студија указује да норадреналин, делујући 
посредством β-адренергичких рецептора, подстиче неуроинфламацију 
у ЕАЕ-у тако што модулише експресију Nrf2 у ћелијама микроглије. 
Такође, она представља могућу полазну основу за будућа транслациона 
фармаколошка истраживања у циљу дизајнирања нових приступа у лечењу 
мултипле склерозе.
PB  - Српска академија наука и уметности
PB  - Друштво имунолога Србије
C3  - Научни скуп - Светски дан имунологије 2021, 29. април 2021. године, Београд
T1  - Блокада β-адренергичких рецептора појачава имунорегулаторна/имунопротективна својства микроглије: испитивање на моделу експерименталног аутоимунског енцефаломијелитиса
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5089
ER  - 

@conference{
author = "Prijić, Ivana and Pilipović, Ivan and Stojić-Vukanić, Zorica and Leposavić, Gordana",
year = "2021",
abstract = "Претпоставља се да дисфункција симпатичког нервног система 
доприноси развоју мултипле склерозе и експерименталног аутоимунског 
енцефаломијелитиса (ЕАЕ). Имајући у виду важност микроглије за 
развој/резолуцију неуроинфламације, испитиван је имуномодулаторни 
потенцијал главног симпатичког медијатора норадреналина коришћењем 
пацовског модела ЕАЕ-а. Резултати су показали да третман пропранололом, 
неселективним блокатором β-адренергичких рецептора, у ефекторској 
фази ЕАЕ-а смањује тежину болести. Ово је корелирало са повећаном 
заступљеношћу микроглије која експримира CX3CR1, кључан молекул за 
њену имуномодулаторну/неуропротективну активност, и њеном појачаном 
експресијом Nrf2 гена, као и гена за хем оксигеназу-1, која се сматра 
ефекторским молекулом анти-инфламаторног CX3CR1/Nrf2 сигналног 
пута. Истраживања in vitro показала су да активација β-адренергичких 
рецептора доводи до нисходне регулације експресије Nrf2 и путем 
независним од CX3CR1. Сходно претходним резултатима, пропранолол 
је повећао фагоцитну способност микроглије, што је корелирало са 
повећањем површинске експресије анти-инфламаторних маркера CD163 
и CD83. Повећање експресије хем оксигеназе-1 праћено је порастом 
заступљености микроглије која синтетише IL-10, а смањењем удела оне 
која експримира проинфламаторне цитокине IL-1β и IL-23. Пропранолол 
је смањио и експресију MCP-1/CCL2 у кичменој мождини. Консекутивно, 
инфилтрација кичмене мождине мијелоидним ћелијама и CD4+ Т-ћелијама 
била је смањена код пацова третираних пропранололом. У складу са свим 
претходним, пропранолол је лимитирао и реактивацију/пролиферацију 
CD4+ Т-лимфоцита и њихову диференцијацију у изузетно патогене IL 17+IFN-γ+GM-CSF+ ћелије. Студија указује да норадреналин, делујући 
посредством β-адренергичких рецептора, подстиче неуроинфламацију 
у ЕАЕ-у тако што модулише експресију Nrf2 у ћелијама микроглије. 
Такође, она представља могућу полазну основу за будућа транслациона 
фармаколошка истраживања у циљу дизајнирања нових приступа у лечењу 
мултипле склерозе.",
publisher = "Српска академија наука и уметности, Друштво имунолога Србије",
journal = "Научни скуп - Светски дан имунологије 2021, 29. април 2021. године, Београд",
title = "Блокада β-адренергичких рецептора појачава имунорегулаторна/имунопротективна својства микроглије: испитивање на моделу експерименталног аутоимунског енцефаломијелитиса",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5089"
}

Prijić, I., Pilipović, I., Stojić-Vukanić, Z.,& Leposavić, G.. (2021). Блокада β-адренергичких рецептора појачава имунорегулаторна/имунопротективна својства микроглије: испитивање на моделу експерименталног аутоимунског енцефаломијелитиса. in Научни скуп - Светски дан имунологије 2021, 29. април 2021. године, Београд
Српска академија наука и уметности..
https://hdl.handle.net/21.15107/rcub_farfar_5089

Prijić I, Pilipović I, Stojić-Vukanić Z, Leposavić G. Блокада β-адренергичких рецептора појачава имунорегулаторна/имунопротективна својства микроглије: испитивање на моделу експерименталног аутоимунског енцефаломијелитиса. in Научни скуп - Светски дан имунологије 2021, 29. април 2021. године, Београд. 2021;.
https://hdl.handle.net/21.15107/rcub_farfar_5089 .

Prijić, Ivana, Pilipović, Ivan, Stojić-Vukanić, Zorica, Leposavić, Gordana, "Блокада β-адренергичких рецептора појачава имунорегулаторна/имунопротективна својства микроглије: испитивање на моделу експерименталног аутоимунског енцефаломијелитиса" in Научни скуп - Светски дан имунологије 2021, 29. април 2021. године, Београд (2021),
https://hdl.handle.net/21.15107/rcub_farfar_5089 .

TY  - JOUR
AU  - Pilipović, Ivan
AU  - Stojić-Vukanić, Zorica
AU  - Prijić, Ivana
AU  - Jasnić, Nebojša
AU  - Leposavić, Gordana
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3509
AB  - Sympathetic dysfunction is suggested to contribute to development of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) alike. Considering important role of microglia in development/resolution of neuroinflammation, contribution of noradrenaline, the key sympathetic end-point mediator, in modulation of microglial phenotypic and functional properties in rat EAE model was examined. The study showed that noradrenaline acting in neurocrine and autocrine/paracrine way might influence microglia during EAE. Propranolol treatment over the effector phase moderated EAE course. This was associated with the increased proportion of microglia expressing CX3CR1, the key molecule in their immunomodulatory/neuroprotective action, and upregulation of CX3CR1 downstream Nrf2 gene. This correlated with the increased heme oxygenase-1 (HO-1) expression and phagocytic capacity of microglia, and their phenotypic changes mirrored in increased proportion of CD163- and CD83-expressing cells. The enhanced HO-1 expression was linked with the decreased proportion of microglial cells expressing IL-1β and IL-23, and possibly IL-6, followed by increased proportion of IL- 10–expressing microglia, and downregulated MCP-1/CCL2 expression. Consistently, spinal cord infiltration with blood-borne myeloid and CD4+ T cells, as well as CD4+ T-cell reactivation/proliferation and differentiation into highly pathogenic IL-17+ cells co-producing IFN-γ and GM-CSF were decreased in propranolol-treated rats compared with saline-injected controls. The in vitro investigations of the effects of noradrenaline on microglia showed that noradrenaline through β-adrenoceptor may influence Nrf2 expression also via CX3CR1-independent route. The study suggests β-adrenoceptor–mediated neuroinflammation-promoting role of noradrenaline in EAE via modulation of microglial Nrf2 expression, and thereby forms the basis for further translational pharmacological research to improve multiple sclerosis therapy.
PB  - Elsevier
T2  - Neurobiology of Disease
T1  - Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia
VL  - 134
DO  - 10.1016/j.nbd.2019.104665
ER  - 

@article{
author = "Pilipović, Ivan and Stojić-Vukanić, Zorica and Prijić, Ivana and Jasnić, Nebojša and Leposavić, Gordana",
year = "2020",
abstract = "Sympathetic dysfunction is suggested to contribute to development of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) alike. Considering important role of microglia in development/resolution of neuroinflammation, contribution of noradrenaline, the key sympathetic end-point mediator, in modulation of microglial phenotypic and functional properties in rat EAE model was examined. The study showed that noradrenaline acting in neurocrine and autocrine/paracrine way might influence microglia during EAE. Propranolol treatment over the effector phase moderated EAE course. This was associated with the increased proportion of microglia expressing CX3CR1, the key molecule in their immunomodulatory/neuroprotective action, and upregulation of CX3CR1 downstream Nrf2 gene. This correlated with the increased heme oxygenase-1 (HO-1) expression and phagocytic capacity of microglia, and their phenotypic changes mirrored in increased proportion of CD163- and CD83-expressing cells. The enhanced HO-1 expression was linked with the decreased proportion of microglial cells expressing IL-1β and IL-23, and possibly IL-6, followed by increased proportion of IL- 10–expressing microglia, and downregulated MCP-1/CCL2 expression. Consistently, spinal cord infiltration with blood-borne myeloid and CD4+ T cells, as well as CD4+ T-cell reactivation/proliferation and differentiation into highly pathogenic IL-17+ cells co-producing IFN-γ and GM-CSF were decreased in propranolol-treated rats compared with saline-injected controls. The in vitro investigations of the effects of noradrenaline on microglia showed that noradrenaline through β-adrenoceptor may influence Nrf2 expression also via CX3CR1-independent route. The study suggests β-adrenoceptor–mediated neuroinflammation-promoting role of noradrenaline in EAE via modulation of microglial Nrf2 expression, and thereby forms the basis for further translational pharmacological research to improve multiple sclerosis therapy.",
publisher = "Elsevier",
journal = "Neurobiology of Disease",
title = "Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia",
volume = "134",
doi = "10.1016/j.nbd.2019.104665"
}

Pilipović, I., Stojić-Vukanić, Z., Prijić, I., Jasnić, N.,& Leposavić, G.. (2020). Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia. in Neurobiology of Disease
Elsevier., 134.
https://doi.org/10.1016/j.nbd.2019.104665

Pilipović I, Stojić-Vukanić Z, Prijić I, Jasnić N, Leposavić G. Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia. in Neurobiology of Disease. 2020;134.
doi:10.1016/j.nbd.2019.104665 .

Pilipović, Ivan, Stojić-Vukanić, Zorica, Prijić, Ivana, Jasnić, Nebojša, Leposavić, Gordana, "Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia" in Neurobiology of Disease, 134 (2020),
https://doi.org/10.1016/j.nbd.2019.104665 . .

TY  - JOUR
AU  - Pilipović, Iivan
AU  - Stojić-Vukanić, Zorica
AU  - Prijić, Ivana
AU  - Leposavić, Gordana
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3503
AB  - The role of stress effector systems in the initiation and progression of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the most commonly used experimental model of MS, has strongly been suggested. To corroborate this notion, alterations in activity of the sympathoadrenal and sympathoneural axes of sympathoadrenal system (a major communication pathway between the central nervous system and the immune system), mirrored in altered release of their end-point mediators (adrenaline and noradrenaline, respectively), are shown to precede (in MS) and/or occur during development of MS and EAE in response to immune cell activation (in early phase of disease) and disease-related damage of sympathoadrenal system neurons and their projections (in late phase of disease). To add to the complexity, innate immunity cells and T-lymphocytes synthesize noradrenaline that may be implicated in a local autocrine/paracrine self-amplifying feed-forward loop to enhance myeloid-cell synthesis of proinflammatory cytokines and inflammatory injury. Furthermore, experimental manipulations targeting noradrenaline/adrenaline action are shown to influence clinical outcome of EAE, in a disease phase-specific manner. This is partly related to the fact that virtually all types of cells involved in the instigation and progression of autoimmune inflammation and target tissue damage in EAE/MS express functional adrenoceptors. Although catecholamines exert majority of immunomodulatory effects through β2-adrenoceptor, a role for α-adrenoceptors in EAE pathogenesis has also been indicated. In this review, we summarize all aforementioned aspects of immunopathogenetic action of catecholamines in EAE/MS as possibly important for designing new strategies targeting their action to prevent/mitigate autoimmune neuroinflammation and tissue damage.
PB  - Frontiers Media S.A.
T2  - Frontiers in Endocrinology
T1  - Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis
VL  - 10
DO  - 10.3389/fendo.2019.00921
ER  - 

@article{
author = "Pilipović, Iivan and Stojić-Vukanić, Zorica and Prijić, Ivana and Leposavić, Gordana",
year = "2020",
abstract = "The role of stress effector systems in the initiation and progression of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the most commonly used experimental model of MS, has strongly been suggested. To corroborate this notion, alterations in activity of the sympathoadrenal and sympathoneural axes of sympathoadrenal system (a major communication pathway between the central nervous system and the immune system), mirrored in altered release of their end-point mediators (adrenaline and noradrenaline, respectively), are shown to precede (in MS) and/or occur during development of MS and EAE in response to immune cell activation (in early phase of disease) and disease-related damage of sympathoadrenal system neurons and their projections (in late phase of disease). To add to the complexity, innate immunity cells and T-lymphocytes synthesize noradrenaline that may be implicated in a local autocrine/paracrine self-amplifying feed-forward loop to enhance myeloid-cell synthesis of proinflammatory cytokines and inflammatory injury. Furthermore, experimental manipulations targeting noradrenaline/adrenaline action are shown to influence clinical outcome of EAE, in a disease phase-specific manner. This is partly related to the fact that virtually all types of cells involved in the instigation and progression of autoimmune inflammation and target tissue damage in EAE/MS express functional adrenoceptors. Although catecholamines exert majority of immunomodulatory effects through β2-adrenoceptor, a role for α-adrenoceptors in EAE pathogenesis has also been indicated. In this review, we summarize all aforementioned aspects of immunopathogenetic action of catecholamines in EAE/MS as possibly important for designing new strategies targeting their action to prevent/mitigate autoimmune neuroinflammation and tissue damage.",
publisher = "Frontiers Media S.A.",
journal = "Frontiers in Endocrinology",
title = "Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis",
volume = "10",
doi = "10.3389/fendo.2019.00921"
}

Pilipović, I., Stojić-Vukanić, Z., Prijić, I.,& Leposavić, G.. (2020). Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. in Frontiers in Endocrinology
Frontiers Media S.A.., 10.
https://doi.org/10.3389/fendo.2019.00921

Pilipović I, Stojić-Vukanić Z, Prijić I, Leposavić G. Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. in Frontiers in Endocrinology. 2020;10.
doi:10.3389/fendo.2019.00921 .

Pilipović, Iivan, Stojić-Vukanić, Zorica, Prijić, Ivana, Leposavić, Gordana, "Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis" in Frontiers in Endocrinology, 10 (2020),
https://doi.org/10.3389/fendo.2019.00921 . .

TY  - CONF
AU  - Pilipović, Ivan
AU  - Prijić, Ivana
AU  - Stojić-Vukanić, Zorica
AU  - Leposavić, Gordana
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5085
AB  - Sympathetic dysfunction was proposed to participate in development of multiple sclerosis and 
its animal model, experimental autoimmune encephalomyelitis (EAE). This may be linked with 
findings indicating that noradrenaline, the key sympathetic end-point mediator, through β adrenoceptor exerts immunomodulatory action. Considering importance of the target tissue for 
the clinical outcome of EAE, the study investigated the effects of propranolol, a non-selective β adrenoceptor blocker, on the disease severity in Dark Agouti rats. Administration of propranolol 
over the effector phase of EAE substantially moderated neurological symptoms of the disease. 
This correlated with the increased proportion of spinal cord microglia expressing CX3CR1, the 
crucial neuroinflammation-limiting molecule, and upregulated expression of Nrf2, the key 
CX3CR1 downstream target gene. Additionally, in spinal cord of propranolol-administered rats 
the expression of heme-oxigenase 1, Nrf2 target gene, was upregulated. Consequently, microglia 
from propranolol-administered rats, exhibited increased proportion of IL-10–expressing cells, 
but decreased those of IL-1β– and IL-23–expressing ones. Propranolol also downregulated the 
IL-6 and MCP-1/CCL2 expression in spinal cord. Furthermore, propranolol affecting 
CXCR1/Nrf2 signaling pathway enhanced microglial phagocytic/endocytic capacity and surface 
expression of anti-inflammatory CD163/CD83 markers. Results from in vitro pharmacological 
study examining influence of noradrenaline/propranolol on functional properties of microglia 
showed that microglia synthesize noradrenaline, which, in turn, through β-adrenoceptor, 
downregulated their Nrf2 expression, in a CX3CR1-independent manner. In accordance with 
microglial shift towards a more anti-inflammatory profile, in spinal cord of propranolol administered rats was found: i) decreased infiltration with blood-borne myeloid and CD4+ T 
cells, and ii) reduced CD4+ T-cell reactivation/proliferation and differentiation into highly 
pathogenic IL-17+ cells co-producing IFN-γ and GM-CSF. The study suggests a 
neuroinflammation-promoting role for central noradrenaline in EAE, via β-adrenoceptor–
mediated modulation of microglial Nrf2 expression. Thus, it points out to a putative target for 
future translational pharmacological research to optimize multiple sclerosis therapy. Funding: 
MPNTR RS (grant number 175050)
PB  - Institute for Biological Research "Siniša Stanković" National Institute of Republic of Serbia
PB  - Immunological Society of Serbia
C3  - Immunology at the confluence of multidisciplinary approaces, Belgrade December 6.-8.  2019, Abstract book
T1  - Propranolol reduced severity of EAE by increasing the expression Nrf2 in microglia
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5085
ER  - 

@conference{
author = "Pilipović, Ivan and Prijić, Ivana and Stojić-Vukanić, Zorica and Leposavić, Gordana",
year = "2019",
abstract = "Sympathetic dysfunction was proposed to participate in development of multiple sclerosis and 
its animal model, experimental autoimmune encephalomyelitis (EAE). This may be linked with 
findings indicating that noradrenaline, the key sympathetic end-point mediator, through β adrenoceptor exerts immunomodulatory action. Considering importance of the target tissue for 
the clinical outcome of EAE, the study investigated the effects of propranolol, a non-selective β adrenoceptor blocker, on the disease severity in Dark Agouti rats. Administration of propranolol 
over the effector phase of EAE substantially moderated neurological symptoms of the disease. 
This correlated with the increased proportion of spinal cord microglia expressing CX3CR1, the 
crucial neuroinflammation-limiting molecule, and upregulated expression of Nrf2, the key 
CX3CR1 downstream target gene. Additionally, in spinal cord of propranolol-administered rats 
the expression of heme-oxigenase 1, Nrf2 target gene, was upregulated. Consequently, microglia 
from propranolol-administered rats, exhibited increased proportion of IL-10–expressing cells, 
but decreased those of IL-1β– and IL-23–expressing ones. Propranolol also downregulated the 
IL-6 and MCP-1/CCL2 expression in spinal cord. Furthermore, propranolol affecting 
CXCR1/Nrf2 signaling pathway enhanced microglial phagocytic/endocytic capacity and surface 
expression of anti-inflammatory CD163/CD83 markers. Results from in vitro pharmacological 
study examining influence of noradrenaline/propranolol on functional properties of microglia 
showed that microglia synthesize noradrenaline, which, in turn, through β-adrenoceptor, 
downregulated their Nrf2 expression, in a CX3CR1-independent manner. In accordance with 
microglial shift towards a more anti-inflammatory profile, in spinal cord of propranolol administered rats was found: i) decreased infiltration with blood-borne myeloid and CD4+ T 
cells, and ii) reduced CD4+ T-cell reactivation/proliferation and differentiation into highly 
pathogenic IL-17+ cells co-producing IFN-γ and GM-CSF. The study suggests a 
neuroinflammation-promoting role for central noradrenaline in EAE, via β-adrenoceptor–
mediated modulation of microglial Nrf2 expression. Thus, it points out to a putative target for 
future translational pharmacological research to optimize multiple sclerosis therapy. Funding: 
MPNTR RS (grant number 175050)",
publisher = "Institute for Biological Research "Siniša Stanković" National Institute of Republic of Serbia, Immunological Society of Serbia",
journal = "Immunology at the confluence of multidisciplinary approaces, Belgrade December 6.-8.  2019, Abstract book",
title = "Propranolol reduced severity of EAE by increasing the expression Nrf2 in microglia",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5085"
}

Pilipović, I., Prijić, I., Stojić-Vukanić, Z.,& Leposavić, G.. (2019). Propranolol reduced severity of EAE by increasing the expression Nrf2 in microglia. in Immunology at the confluence of multidisciplinary approaces, Belgrade December 6.-8.  2019, Abstract book
Institute for Biological Research "Siniša Stanković" National Institute of Republic of Serbia..
https://hdl.handle.net/21.15107/rcub_farfar_5085

Pilipović I, Prijić I, Stojić-Vukanić Z, Leposavić G. Propranolol reduced severity of EAE by increasing the expression Nrf2 in microglia. in Immunology at the confluence of multidisciplinary approaces, Belgrade December 6.-8.  2019, Abstract book. 2019;.
https://hdl.handle.net/21.15107/rcub_farfar_5085 .

Pilipović, Ivan, Prijić, Ivana, Stojić-Vukanić, Zorica, Leposavić, Gordana, "Propranolol reduced severity of EAE by increasing the expression Nrf2 in microglia" in Immunology at the confluence of multidisciplinary approaces, Belgrade December 6.-8.  2019, Abstract book (2019),
https://hdl.handle.net/21.15107/rcub_farfar_5085 .