Long term immune stability is under the regulatory control of the autonomous nervous system. The two branches of the autonomic nervous system coordinate and sequence the phases of the immune response. Catecholamines released during sympathetic activation come into contact with adrenergic receptors on immune cells, driving the adaptive response to infection or inflammation. Stimulation of α-adrenergic receptors is associated with the initial, rapid, pro-inflammatory innate response. Stimulation of β-adrenergic receptors, in contrast, is implicated in a more specialized, context-dependent modulation of inflammatory signaling, reprogramming of immune cell proliferation, as well as immune cell differentiation and surveillance.
The resolution phase of the inflammatory response is governed by parasympathetic activation, the key determinant of vagal tone. Ensuing synthesis of acetylcholine acts on the muscarinic and nicotinic receptors expressed on immune cells to trigger the gradual re-establishment of immune homeostasis. Without the timely arousal of the parasympathetic nervous system, inflammation can become prolonged and perpetuate a heightened state of immune hyper-activation and loss of proficiency.
Hematopoiesis is critically regulated by the signals emanating from the sympathetic nervous system. Noradrenergic input to lymphoid organs dictates the proliferation, circulation, fate, and activity of immune cells. Adrenergic receptors are similarly found on endothelial and stromal vascular cells. β₁-β₃ adrenergic receptors are variably expressed across immune cell subsets, and the cascading effects following their stimulation is highly context- and cell-specific. β₂-adrenergic receptor signaling serves as the core immunoregulatory axis, contributing to an anti-inflammatory, immunotolerant milieu in both innate and adaptive immunity. However, depending on the ligand, activation state, timing, and disease status, β-adrenergic signaling can produce distinct outcomes.
The picture becomes more complex in relation to the Th17/Treg balance due to the strong influence of circulating cytokines. In CD4+ T-cells, an inflammatory environment will push toward Th17 polarization, STAT3 activation, and IL-17 synthesis. Anti-inflammatory IL-2 signaling, on the contrary, signals through STAT5 to restrain Th17 differentiation in favor of FoxP3 expression and Treg polarization. Intracellular metabolic signaling through the PI3K-Akt-mTOR pathway can also antagonize FoxP3 induction and aggravate Th17 polarization. β₂-adrenergic receptor signaling potentiates Treg cell activity of committed CD4+FoxP3+ Treg cells via upregulation of cAMP-PKA-CREB and CTLA-4. However, autocrine catecholamines produced by T cells can sustain the generation of IL-17, as evidenced by β-adrenergic signaling in differentiated Th17 cells prompting further IL-17 transcription. In these contexts, β-receptor blockade can attenuate IL-17 A+ Th17 cells while bolstering FoxP3+ Tregs.
The nuance of adrenergic-mediated immunomodulation is perfectly demonstrated in a state of low-grade inflammation that commonly manifests with age. The stress response involves a delicate balance between transient, pro-inflammatory IL-6 synthesis and leukocyte mobilization, and a quick transition into an anti-inflammatory phase. According to the fertile field hypothesis, protracted, accumulated exposure to stress stimuli can consequently lead to autonomic dysregulation. Viral exposure, along with metabolic, neuroendocrine, genetic, and inflammatory factors, can lower the threshold for immune hyper-activation and diminished immunotolerance.
Persistent sympathetic nervous system arousal and a complementary loss of parasympathetic nervous system counterbalance causes acute, localized inflammatory signaling to progress systemically, instigating chronic immune activation and hindering inflammatory resolution. In such circumstances, β-adrenergic receptors in the vasculature and lymphoid organs are desensitized to β₂-signaling that ordinarily quells immune activation and modulates cytokine-related inflammatory cascades. Additionally, a low-grade inflammatory setting marked by pro-inflammatory cytokines activates STAT3 implicated in Th17 polarization. Attenuation of anti-inflammatory and tolerogenic pathways fosters a permissive environment for autoantibody formation and downstream vulnerability to autoimmune and autoinflammatory disease.
The stress response is a highly dynamic, complex, and vital component of immune system function. A considered approach is required to astutely discriminate between a self-limiting, acute sympathetic response and that of excessive adrenergic exposure. Adrenergic signaling behaves as a regulatory checkpoint for IL-17-driven immune activation. The ligand and other contextual characteristics profoundly influence the consequence of β-adrenergic receptor engagement. Activation can paradoxically suppress certain inflammatory genes while upregulating the transcription of others in a temporal fashion. Aging, chronic inflammation, and post-viral conditions create a landscape of vulnerability, with β-adrenergic signaling behaving as a key modulatory axis of immunity.
Giunta S, Sabbatinelli J, Olivieri F, Giuliani A. Aging-related autonomic nervous system imbalance and adrenergic regulation of immunity: Implications for inflammaging, autoimmunity, and long COVID. Front Neuroendocrinol. Published online June 24, 2026. doi:10.1016/j.yfrne.2026.101269