AI–Assisted Evolving Concept Article
Introduction
Interleukin-17 (IL-17) and the T-helper 17 (Th17) cells that predominantly produce it are pivotal components of the immune system, orchestrating both protective immunity and pathological inflammation. Identified as a distinct CD4+ T-cell lineage in the mid-2000s, Th17 cells secrete IL-17A, IL-17F, IL-21, and IL-22, cytokines critical for defending against extracellular pathogens, particularly at mucosal surfaces. However, when dysregulated, Th17 cells drive chronic inflammation and autoimmunity, contributing to diseases such as psoriasis, rheumatoid arthritis, and multiple sclerosis.
Recent research has illuminated a broader role for IL-17 and Th17 cells, revealing intricate interactions with the nervous and endocrine systems. These interactions involve neuromediators, neurotransmitters, hormones, and direct nerve-immune communications, influencing disease onset, progression, and severity. This overview synthesizes evidence from multiple studies to explore how these neuro-immune-endocrine interactions contribute to the pathogenesis of diverse human diseases, offering insights into potential therapeutic avenues.
Neuromediators and Neurotransmitters
Neuromediators and neurotransmitters bridge the nervous and immune systems, modulating Th17 activity. A prominent example is substance P, an undecapeptide of the tachykinin family, known for its roles in pain perception and stress responses. In generalized anxiety disorder (GAD), substance P promotes a Th17 phenotype, as demonstrated in a study where peripheral blood mononuclear cells from GAD patients, when cultured with substance P, exhibited increased IL-17 and TNF-α production (Ref. 1) without enhancing Th1 cytokines like IFN-γ, unlike in healthy controls.
This shift suggests that substance P, released by nerve endings under stress, amplifies Th17-driven inflammation, potentially explaining the heightened infection susceptibility and autoimmune disease exacerbations in chronically stressed individuals. The glucocorticoid insensitivity observed in GAD further underscores a dysregulated neuro-immune axis, where substance P sustains Th17 hyperactivity despite immunosuppressive signals. This mechanism may extend to other stress-related or pain-associated conditions, warranting further investigation into neuromediator-targeted therapies.
Hormones
Hormones, particularly adipokines from adipose tissue, significantly influence Th17 responses, linking metabolic status to immune dysregulation. Leptin, a hormone regulating energy balance, promotes Th17 differentiation by inducing the transcription factor RORγt. In systemic lupus erythematosus (SLE), leptin increased Th17 cell numbers in a dose-dependent manner (Ref. 2) in human CD4+ T-cell cultures and correlated positively with plasma IL-17 levels in SLE patients. In lupus-prone mice, leptin enhanced Th17 responses, highlighting its pro-inflammatory role in autoimmunity.
Similarly, adiponectin, typically considered anti-inflammatory, exhibits a maladaptive effect in rheumatoid arthritis. In collagen-induced arthritis (CIA) mice, intra-articular adiponectin injection aggravated joint inflammation and bone erosion by upregulating Th17-related cytokines (IL-17, IL-22, IL-23) and RANKL expression (Ref. 3). This suggests that in specific inflammatory contexts, adiponectin shifts from protective to pathogenic, enhancing Th17 activity and osteoclastogenesis.
In Hashimoto’s thyroiditis, an autoimmune thyroid disease, Th17 cells may interact with thyroid hormones bidirectionally. Higher serum IL-17 and IL-23 levels in euthyroid patients compared to hypothyroid ones suggest a more significant Th17 role in early disease stages (Ref. 4), possibly triggered by initial thyroid hormone.
Although direct correlations between thyroid hormone levels and Th17 cytokines were not established, this hints at an immune-endocrine feedback loop where hormonal changes modulate Th17 activity, contributing to thyroid autoimmunity progression. These findings underscore how metabolic and endocrine factors, through hormones like leptin, adiponectin, and thyroid hormones, can drive Th17-mediated pathology, offering potential targets for modulating inflammation in autoimmune diseases.
Direct Nerve-Immune Interactions
Direct interactions between immune cells and the nervous system, particularly via nerves and nerve endings, are evident in several conditions. In Guillain-Barré Syndrome (GBS), an acute inflammatory neuropathy, Th17 cells dominate inflamed peripheral nerves during the acute phase (Ref. 5), with elevated circulating Th17 and Th22 cells and plasma IL-17 and IL-22 levels. Intravenous immunoglobulin (IVIg) therapy downregulates these cells and cytokines, alleviating clinical symptoms, suggesting that Th17 cells directly target nerve tissues, possibly in response to neural signals or post-infectious triggers like Campylobacter jejuni. This nerve-immune crosstalk highlights IL-17 as a pathogenic cytokine in GBS, with therapeutic implications for targeting Th17 pathways.
Chronic urticaria, marked by persistent hives, exhibits a Th2/Th17 shift in skin lesions, with increased Th17 cell frequency compared to normal skin (Ref. 6). Given the skin’s rich innervation, this suggests that nerve endings may interact with Th17 cells locally, amplifying inflammation. The lack of significant mast cell differences in autoimmune versus non-autoimmune cases further implicates Th17 cells as key drivers, potentially modulated by neural mediators like substance P.
In fibromyalgia, a condition of widespread pain without a clear inflammatory basis, high plasma IL-17 levels correlate with pain, depression, and anxiety indices (Ref. 7).This raises the possibility of Th17-mediated neuroinflammation or altered pain processing via interactions with the central nervous system, though mechanisms remain speculative.
Similarly, in atherosclerosis, Chlamydophila pneumoniae phospholipase D induces Th17 inflammation within plaques, upregulating chemokines and adhesion molecules (Ref. 8) in endothelial cells. While not directly neural, the vascular system’s autonomic innervation suggests potential nerve-immune interplay influencing Th17 activity and plaque instability.
Developmental Aspects
The impact of Th17 cells extends to neurodevelopmental disorders, as seen in a mouse model of autism. Maternal immune activation (MIA) during pregnancy, induced by poly(I:C), increases fetal IL-17 levels (Ref. 9), leading to disorganized cortical cytoarchitecture and autism-like behaviors in offspring. Blocking maternal IL-17 with antibodies prevents these outcomes, indicating that Th17-derived IL-17 directly affects fetal brain development. This suggests a critical window where maternal immune responses, potentially modulated by stress-related neuromediators or hormones, influence neurodevelopmental trajectories via IL-17, with implications for understanding autism spectrum disorders in humans.
Therapeutic Implications
The therapeutic potential of targeting IL-17 and Th17 cells is exemplified in ankylosing spondylitis, a chronic inflammatory arthritis. Secukinumab, an IL-17A inhibitor, significantly reduces disease signs and symptoms, with sustained efficacy over years (Ref. 10), offering an alternative to TNF inhibitors for patients with inadequate responses. This success underscores IL-17’s pathogenic role and suggests that similar strategies could benefit other Th17-driven conditions. Modulating neuromediators like substance P or hormones like leptin and adiponectin could also attenuate Th17 activity, providing novel approaches to manage inflammation across these diseases.
Conclusion
IL-17 and Th17 cells are central to a spectrum of human diseases, from autoimmune and inflammatory conditions to neurodevelopmental and psychiatric disorders. Their interactions with the nervous and endocrine systems—via neuromediators like substance P, hormones such as leptin and adiponectin, and direct nerve-immune contacts—amplify their pathogenic potential. In GBS and chronic urticaria, Th17 cells target nerve-rich tissues; in SLE and arthritis, adipokines drive Th17 responses; in anxiety, substance P enhances Th17 inflammation; and in autism, maternal IL-17 disrupts fetal brain development. These findings highlight a complex neuro-immune-endocrine network that shapes disease pathogenesis.
For scientists and clinicians, this interplay offers new diagnostic and therapeutic opportunities. IL-17 inhibitors like secukinumab demonstrate efficacy, while targeting upstream modulators (e.g., substance P, adipokines) could further refine treatments. However, challenges remain, including elucidating precise mechanisms and translating findings into clinical practice. Future research should focus on these interactions’ molecular underpinnings and their therapeutic modulation, potentially revolutionizing management strategies for Th17-associated diseases.
Professional AI assistance:
The production of this article was assisted by an Artificial Intelligence (AI). The articles used as references were manually selected with the help of Zlatin Balevsky who also formulated the instructions given to the AI. Balevsky Research Services LTD (https://balevsky.ai) offers consulting services to scientists interested in leveraging AI in their research.
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