Role of the Sympathetic Nervous System in Mild Chronic Inflammatory Diseases: Focus on Osteoarthritis

Abstract

The sympathetic nervous system (SNS) is a major regulatory mediator connecting the brain and the immune system that influences accordingly inflammatory processes within the entire body. In the periphery, the SNS exerts its effects mainly via its neurotransmitters norepinephrine (NE) and epinephrine (E), which are released by peripheral nerve endings in lymphatic organs and other tissues. Depending on their concentration, NE and E bind to specific α- and β-adrenergic receptor subtypes and can cause both pro- and anti-inflammatory cellular responses. The co-transmitter neuropeptide Y, adenosine triphosphate, or its metabolite adenosine are also mediators of the SNS. Local pro-inflammatory processes due to injury or pathogens lead to an activation of the SNS, which in turn induces several immunoregulatory mechanisms with either pro- or anti-inflammatory effects depending on neurotransmitter concentration or pathological context. In chronic inflammatory diseases, the activity of the SNS is persistently elevated and can trigger detrimental pathological processes. Recently, the sympathetic contribution to mild chronic inflammatory diseases like osteoarthritis (OA) has attracted growing interest. OA is a whole-joint disease and is characterized by mild chronic inflammation in the joint. In this narrative article, we summarize the underlying mechanisms behind the sympathetic influence on inflammation during OA pathogenesis. In addition, OA comorbidities also accompanied by mild chronic inflammation, such as hypertension, obesity, diabetes, and depression, will be reviewed. Finally, the potential of SNS-based therapeutic options for the treatment of OA will be discussed.

Osteoarthritis patients exhibit an autonomic dysfunction with indirect sympathetic dominance

“…An increased LF/HF ratio, as detected in early OA patients, has already been reported in RA patients [44]. Moreover, the SNS is known to promote mild chronic inflammation in OA [9]. The declined sympathetic and parasympathetic activity together with the occurring imbalance of both systems indicate an autonomic dysfunction in OA.…”

“…Furthermore, OA-related perceived pain and stress levels are potentially linked to this autonomic dysfunction. These findings become even more relevant when taking into account that an increased sympathetic activity and low-grade chronic inflammation reinforce each other in OA but also in OA comorbidities, such as hypertension, obesity, diabetes, and depression [9]. Consequently, these findings not only contribute to a more comprehensive understanding of the autonomic aspects of OA pathogenesis but also provide a link to the major OA comorbidities, shedding light on potential future therapeutic strategies targeting the ANS.…”

“…Recently, a possible autonomic nervous system (ANS) dysfunction with a shift towards a more prominent Sohn et al Journal of Translational Medicine (2024) 22:467 sympathetic nervous system (SNS), gained prominence in OA research as an additional risk factor [4]. The ANS plays a critical role in joint homeostasis and is implicated in the pathogenesis of OA [8][9][10]. Next to the enteric nervous system, the ANS comprises the SNS and the parasympathetic nervous system (PNS), which often exert antagonistic effects.…”

“…In a healthy environment, sympathetic and parasympathetic effects are tightly coordinated and balanced, providing homeostasis for various physiological functions such as heartbeat, blood pressure, respiration, digestion, temperature regulation, and sexual arousal [14,15]. Moreover, the ANS is a pivotal regulatory mediator between the brain and the immune system, with SNS activity having a particularly profound influence on inflammatory processes [9]. Thus, an altered autonomic balance could increase vulnerability to inflammatory stimuli or impair the ability to combat inflammatory pathologies, for example during OA [4].…”

Sleep duration and the risk of new-onset arthritis in middle-aged and older adult population: results from prospective cohort study in China

“…Consequently, local cells and immune cells acquire an endogenous ability to produce catecholamines for fine-tuning inflammation responses that have lost central control by the brain. However, if this process persists akin to chronic inflammation, sustained impairment in neural breakdown metabolism will expedite arthritis onset ( 40 , 41 ).…”