Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia

Pilipović, Ivan; Stojić-Vukanić, Zorica; Prijić, Ivana; Jasnić, Nebojša; Leposavić, Gordana

doi:10.1016/j.nbd.2019.104665

Cited by 16 publications

(29 citation statements)

References 98 publications

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“…Consistently, compared with saline-injected controls, in propranolol-treated rats the frequencies of IL-1β-and IL-23-expressing cells among microglia, and microglia expression level of IL-6 and CCL-2, the chemokine recruiting inflammatory monocytes and T-cells to the sites of inflammation (110), was decreased (45). Additionally, in accordance with role of CX3CR1 in regulation of the expression of TAM receptors (111), which are essential in apoptotic cell phagocytosis (112), so that their deficiency is linked with autoimmune disease progression (110), the frequency of phagocytic cells among microglia was significantly increased in propranolol-treated rats (45). As expected (9,113,114), this correlated with the increased proportion of anti-inflammatory CD163-and IL-10-expressing microglia (45).…”

Section: Animal Datamentioning

confidence: 62%

“…The study encompassing dogs suffering from EAE showed that cerebrospinal fluid and white matter noradrenaline levels rise early after the immunization, but decrease in the clinical phase of the disease (91). Consistently, decline in SC and/or brainstem noradrenaline concentration was found at the peak of EAE in Lewis and Dark Agouti (DA) rats (45,(92)(93)(94). Noradrenaline concentration in SC also decreased with EAE progression in C57BL/6 mice (72,95).…”

Section: Animal Datamentioning

confidence: 73%

“…Nrf2 recognizes an enhancer sequence termed antioxidant response element that is present in the regulatory regions of over 250 genes (108), and is implicated in the modulation of inflammation through crosstalk with the transcription factor NF-κB, the principal regulator of inflammation (109). Consistently, compared with saline-injected controls, in propranolol-treated rats the frequencies of IL-1β-and IL-23-expressing cells among microglia, and microglia expression level of IL-6 and CCL-2, the chemokine recruiting inflammatory monocytes and T-cells to the sites of inflammation (110), was decreased (45). Additionally, in accordance with role of CX3CR1 in regulation of the expression of TAM receptors (111), which are essential in apoptotic cell phagocytosis (112), so that their deficiency is linked with autoimmune disease progression (110), the frequency of phagocytic cells among microglia was significantly increased in propranolol-treated rats (45).…”

Section: Animal Datamentioning

confidence: 74%

“…Propranolol treatment starting 3 days before immunization moderated clinical and histological picture of EAE in DA rats (102), whereas the treatment beginning at immunization prolonged the disease duration in Lewis rats (101). When administered over effector phase of EAE to Lewis rats, propranolol exacerbated the disease (103), or produced no effect (101), while propranolol treatment in DA rats starting before the onset of clinical EAE decreased the disease severity (45). Given that propranolol crosses the BBB (104), the latter findings were consistent with data indicating that chemical depletion of central noradrenaline starting before the effector phase of EAE may remove an effector amplification mechanism leading to suppression of the paralysis (97).…”

Section: Animal Datamentioning

confidence: 99%

“…Catecholamines exert immunomodulatory effects through β-and α-adrenoceptors expressed on almost all types of immune cells, but majority of their effects are β 2 -adrenoceptormediated (18,25,43,(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60). Monocytes/macrophages, together with dendritic cells, constitute the mononuclear phagocyte system, which plays a key role in maintaining tissue integrity, its restoration after injury, and the initiation, direction and resolution of innate and adaptive immunity.…”

Section: Introductionmentioning

confidence: 99%

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Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

et al. 2020

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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 β 2-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.

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Section: Animal Datamentioning

confidence: 62%

Section: Animal Datamentioning

confidence: 73%

Section: Animal Datamentioning

confidence: 74%

Section: Animal Datamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

et al. 2020

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Pathophysiological basis and promise of experimental therapies for Gulf War Illness, a chronic neuropsychiatric syndrome in veterans

et al. 2023

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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

et al. 2022

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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 dimorphism 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 trafficking 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.

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Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia

Cited by 16 publications

References 98 publications

Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Pathophysiological basis and promise of experimental therapies for Gulf War Illness, a chronic neuropsychiatric syndrome in veterans

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

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