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 target for treatment. Based on our findings in inflammatory arthritis and our understanding of common inflammatory process that are used by the immune system across all IMIDs, novel strategies to restore SNS homeostasis are expected to provide safe, cost-effective approaches to treat IMIDs, lower comorbidities, and increase longevity.
Highlights
Immune-mediated inflammatory disease (IMID) is a concept used to describe a group of highly prevalent, disabling chronic inflammatory conditions that cause end-organ tissue damage and that share the activation of common inflammatory pathways and the dysregulation of the normal adaptive immune response [1]
We focus on rheumatoid arthritis (RA) because the effects of the sympathetic nervous system (SNS) on chronic inflammation and cell-mediated immune responses have been most extensively studied in this IMID, and it is an IMID of high prevalence
Findings presented in a prototypical IMID model lend support to our hypothesis that chronic high splenic sympathetic nerve activity (SNA) before disease onset precipitates SNS pathology and can sabotage the normal resolution of cellular immunity and subsequent return to an anti-inflammatory state
Summary
Immune-mediated inflammatory disease (IMID) is a concept used to describe a group of highly prevalent, disabling chronic inflammatory conditions that cause end-organ tissue damage and that share the activation of common inflammatory pathways and the dysregulation of the normal adaptive immune response [1]. SNS dysregulation in the presence of unresolved immune activation has been proposed as a key triggering factor for onset and disease worsening in IMIDs (Figure 2) The consequences of these chronic conditions induce cyclic and cascading hyper-sympathetic nerve activity (SNA) activity, systemic inflammation and localized immune activation in tissues targeted by the IMID. Spleen function is regulated by all major stress pathways, and serves as a crossroad in the pathophysiology of RA and other IMIDs. The orchestration of the immune response in the spleen determines in a major way, both the systemic inflammatory response and the localized immune dysfunction in the affected targets in RA and other IMIDs. Since the SNS regulates systemic inflammation and immunity largely via its regulation of splenic immune functions, and maintains visceral organ allostasis, our findings raise the question: “How does hyper-sympathetic nerve activity in the spleen conspire with the immune system to induce or drive an IMID, inflammatory arthritis? We critically interpret our findings and their consequences for Th cell development, Th cell function, systemic inflammation, and their clinical significance
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