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

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 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.

Sex-specific remodeling of T-cell compartment with aging: Implications for rat susceptibility to central nervous system autoimmune diseases

“…3). Indeed, we have shown that β-adrenoceptor blockade reduces the incidence and severity of EAE [294][295][296].…”

“Neuroimmunoendocrinology” in Children with Rheumatic Diseases: How Glucocorticoids Are the Orchestra Director

“…Furthermore, cells regulating innate immunity and T lymphocytes can secrete noradrenaline that may be involved in a local autocrine and paracrine self-amplifying feed-forward loop enhancing proinflammatory cytokines synthesis by myeloid cells and inflammatory damage in experimental autoimmune encephalomyelitis (EAE) and in multiple sclerosis (MS). All cell types involved in the autoimmune inflammation and targeted tissue damage in autoimmune central nervous system diseases express receptors for catecholamines [4]. Catecholamines exert most of their immunomodulatory actions through β 2 -adrenoreceptors; however, α-adrenoreceptors can play a role in the diseases [4].…”

“…All cell types involved in the autoimmune inflammation and targeted tissue damage in autoimmune central nervous system diseases express receptors for catecholamines [4]. Catecholamines exert most of their immunomodulatory actions through β 2 -adrenoreceptors; however, α-adrenoreceptors can play a role in the diseases [4].…”

Pathophysiological functions of semaphorins in the sympathetic nervous system

“…In autoimmune diseases, catecholamines modulate disease states in a phase-dependent manner. For example, in an experimental autoimmune encephalomyelitis (EAE) model, NE acts differently in the central and peripheral nervous systems at the induction and effector phases [ 36 ]. In the induction phase, β2-adrenergic signaling promotes microglial inflammation at spinal cord while suppresses CD4 + T-cell proliferation and skewing toward Th17 at the draining lymph nodes.…”

“…In the induction phase, β2-adrenergic signaling promotes microglial inflammation at spinal cord while suppresses CD4 + T-cell proliferation and skewing toward Th17 at the draining lymph nodes. In the effector phase, α1-adrenergic signaling activates microglia, macrophages, and dendritic cells and suppresses regulatory T-cell responses at both sites [ 36 ]. Chronic cold-stress stimulation ameliorates neuroinflammation by suppressing antigen presentation by monocytes in the bone marrow via β3-adrenergic receptor signaling [ 37 ].…”