Sympathetic Nerve Hyperactivity in the Spleen: Causal for Nonpathogenic-Driven Chronic Immune-Mediated Inflammatory Diseases (IMIDs)?

Abstract

Immune-Mediated Inflammatory Diseases (IMIDs) is a descriptive term coined for an eclectic group of diseases or conditions that share common inflammatory pathways, and for which there is no definitive etiology. IMIDs affect the elderly most severely, with many older individuals having two or more IMIDs. These diseases include, but are not limited to, type-1 diabetes, obesity, hypertension, chronic pulmonary disease, coronary heart disease, inflammatory bowel disease, and autoimmunity, such as rheumatoid arthritis (RA), Sjőgren’s syndrome, systemic lupus erythematosus, psoriasis, psoriatic arthritis, and multiple sclerosis. These diseases are ostensibly unrelated mechanistically, but increase in frequency with age and share chronic systemic inflammation, implicating major roles for the spleen. Chronic systemic and regional inflammation underlies the disease manifestations of IMIDs. Regional inflammation and immune dysfunction promotes targeted end organ tissue damage, whereas systemic inflammation increases morbidity and mortality by affecting multiple organ systems. Chronic inflammation and skewed dysregulated cell-mediated immune responses drive many of these age-related medical disorders. IMIDs are commonly autoimmune-mediated or suspected to be autoimmune diseases. Another shared feature is dysregulation of the autonomic nervous system and hypothalamic pituitary adrenal (HPA) axis. Here, we focus on dysautonomia. In many IMIDs, dysautonomia manifests as an imbalance in activity/reactivity of the sympathetic and parasympathetic divisions of the autonomic nervous system (ANS). These major autonomic pathways are essential for allostasis of the immune system, and regulating inflammatory processes and innate and adaptive immunity. Pathology in ANS is a hallmark and causal feature of all IMIDs. Chronic systemic inflammation comorbid with stress pathway dysregulation implicate neural-immune cross-talk in the etiology and pathophysiology of IMIDs. Using a rodent model of inflammatory arthritis as an IMID model, we report disease-specific maladaptive changes in β2-adrenergic receptor (AR) signaling from protein kinase A (PKA) to mitogen activated protein kinase (MAPK) pathways in the spleen. Beta2-AR signal “shutdown” in the spleen and switching from PKA to G-coupled protein receptor kinase (GRK) pathways in lymph node cells drives inflammation and disease advancement. Based on these findings and the existing literature in other IMIDs, we present and discuss relevant literature that support the hypothesis that unresolvable immune stimulation from chronic inflammation leads to a maladaptive disease-inducing and perpetuating sympathetic response in an attempt to maintain allostasis. Since the role of sympathetic dysfunction in IMIDs is best studied in RA and rodent models of RA, this IMID is the primary one used to evaluate data relevant to our hypothesis. Here, we review the relevant literature and discuss sympathetic dysfunction as a significant contributor to the pathophysiology of IMIDs, and then discuss a novel targ...

Immunohistochemical analysis of the mouse celiac ganglion: An integrative relay station of the peripheral nervous system

“…Prevertebral ganglia such as the celiac ganglia play a vital role in regulating the function of many effector tissues such as the gastrointestinal tract (Westfall & Westfall, ). Recent work has also highlighted the importance of the celiac ganglion in circuitry that modulates the immune system through its noradrenergic projections to the spleen (Andersson & Tracey, ; Bellinger & Lorton, ; Hoover, ). While it is recognized that prevertebral ganglia are complex integrative centers (Fasano & Niel, ; Miolan & Niel, ), our knowledge regarding the neurochemical anatomy of mouse celiac ganglion was sparse.…”

“…Prevertebral ganglia such as the celiac ganglia play a vital role in regulating the function of many effector tissues such as the gastrointestinal tract (Westfall & Westfall, 2006). Recent work has also highlighted the importance of the celiac ganglion in circuitry that modulates the immune system through its noradrenergic projections to the spleen (Andersson & Tracey, 2012;Bellinger & Lorton, 2018;Hoover, 2017).…”

“…Activated sympathetic neurons provide inhibitory feedback to appropriate regions of the proximal gut, completing enteroenteric and enterogastric reflex arcs that are topographically organized to provide coordination of activity between different regions (Fasano & Niel, 2009;Miolan & Niel, 1996). While other target organs of the celiac ganglia have received far less attention, there is substantial current interest in the spleen as an important site for neural regulation of immune function by the sympathetic nervous system (Andersson & Tracey, 2012;Bellinger & Lorton, 2018;Hoover, 2017;Komegae et al, 2018;Martelli, Mckinley, & McAllen, 2014).…”

The sympathetic nervous system in acute kidney injury

“…9 Sustained sympathetic overactivity causes either β 2 -adrenoceptor downregulation or a switch to so-called non-canonical β 2 -adrenoceptor-dependent signal transduction via extracellular signal-regulated (ERK)/mitogen-activated protein kinase (MAPK) pathways supporting a splenic pro-inflammatory cytokine pattern and corresponding changes in splenic macrophage and lymphocyte subpopulations. 9 Sustained sympathetic overactivity causes either β 2 -adrenoceptor downregulation or a switch to so-called non-canonical β 2 -adrenoceptor-dependent signal transduction via extracellular signal-regulated (ERK)/mitogen-activated protein kinase (MAPK) pathways supporting a splenic pro-inflammatory cytokine pattern and corresponding changes in splenic macrophage and lymphocyte subpopulations.…”

“…1,5 Pathologic states that lead to AKI are frequently associated with acute activation of the sympathetic nervous system (SNS) and the development of AKI in turn may cause sympathetic activation. [7][8][9] The present article reviews the current state on the role of SNS overactivity in AKI focusing on renal ischaemia reperfusion (IR). 6 Evidence is accumulating that interactions between the autonomic nervous system and the immune system are involved in the pathogenesis of multiple forms of organ damage.…”