---
title: "Neural-Immune-Cardiovascular Axis: Mechanisms and Therapeutic Targets in Cardiovascular Disease"
id: "frontiers-in-immunology-13-neural-immune-cardiovascular-axis-from-mechanistic-crosstalk-to-therapeutic"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-13-neural-immune-cardiovascular-axis-from-mechanistic-crosstalk-to-therapeutic"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1886102"
published_at: "2026-07-22T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Neural-Immune-Cardiovascular Axis: Mechanisms and Therapeutic Targets in Cardiovascular Disease
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-13-neural-immune-cardiovascular-axis-from-mechanistic-crosstalk-to-therapeutic
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1886102)
- **Published At:** 2026-07-22T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The **neural-immune-cardiovascular axis** is a complex bidirectional communication network involving the nervous, immune, and vascular systems that maintains cardiovascular homeostasis and contributes to disease. - This axis operates through pathways including sympathetic and parasympathetic nervous systems, sensory neurons, the hypothalamic-pituitary-adrenal (HPA) axis, and immune cell signaling. - In cardiovascular diseases such as **atherosclerosis, hypertension**, and **heart failure**, dysregulation of this axis leads to chronic inflammation, vascular dysfunction, and disease progression. - Sympathetic nerve activation releases norepinephrine acting on various adrenergic receptors, influencing immune cell function, vascular tone, and inflammation. - Parasympathetic activity via the vagus nerve and acetylcholine exerts anti-inflammatory and cardioprotective effects. - Sensory neurons relay signals between cardiovascular tissue and the brain while modulating local immune responses through neuropeptides. - The HPA axis modulates immune and cardiovascular function through glucocorticoids linking psychosocial stress to inflammatory pathology. - Immune cells express receptors for neural signals and secrete cytokines (e.g., TNF-α, IL-6, IL-17) that affect vascular cells and nervous system feedback. - Feedback loops between cytokines and neural pathways contribute to neuroimmune dysregulation in cardiovascular pathology. - Organ-specific interactions, notably in the spleen, enhance neuroimmune crosstalk influencing systemic inflammation and cardiovascular disease. - The adaptive immune system, especially T cell subsets, is modulated by neural inputs affecting inflammatory balance in cardiovascular disease. - The vascular system integrates neural and immune signals to regulate vascular tone, permeability, and inflammatory responses crucial to cardiovascular health and disease. - Therapeutic strategies targeting this axis are emerging but face challenges due to the complexity of interactions and systemic effects.
## Clinical Analysis & Structured Key Points
About us All journals All articles Submit manuscript Submit data Search Frontiers in Immunology Sections Articles Research Topics Editorial board About journal Published in Frontiers in Immunology Multiple Sclerosis and Neuroimmunology 7 impact factor 11.3 citescore Part of a Research Topic Neuroinflammation and immune mechanisms in brain disorders Submission open 1724 views 4 articles Editor & Reviewers Edited by W S Wei Shan Reviewed by Q R Qian Ren Z Z Zhen Zhang H Z Heng Zhang N L Nicola Laera Outline Abstract 1 Introduction 2 Core components and fundamental communication mechanisms of the neural-immune-caridiovascular axis 3 Mechanisms of the neural-immune-cardiovascular axis in atherosclerosis 4 The role of the neural-immune-vascular axis in the pathogenesis and development of hypertension 5 The neural-immune-cardiovascular axis and the vicious cycle of heart failure 6 Therapeutic strategies targeting the neuro-immune-cardiovascular axis 7 Challenges and future prospects 8 Conclusion Author contributions Funding Conflict of interest Generative AI statement Publisher’s note References Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Table 1 Core components of the neural-immune-vascular axis in cardiovascular diseases. View in article Table 2 Key clinical trials targeting the neural-immune-vascular axis. View in article REVIEW article Front. Immunol., 22 July 2026 Sec. Multiple Sclerosis and Neuroimmunology Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1886102 Neural-immune-cardiovascular axis: from mechanistic crosstalk to therapeutic targets in cardiovascular disease J C Junkang Cheng 1† S G Shuang Gao 2† H Z Haowei Zhang 1 W G Wei Gao 1 Z M Zeyuan Mei 1 X L Xiaoling Liu 1 J G Jocelyn Gao 3 C G Chenghu Guo 1* G A Guipeng An 1* 1. State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research of Ministry of Education (MOE), National Health Commission (NCH), Chinese Academy of Medical Sciences (CAMS) and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China 2. Department of Cardiology, Jinan First People’s Hospital, Jinan, China See more Abstract The neural-immune-cardiovascular axis represents an emerging and highly integrated physiological and pathophysiological concept, describing a complex bidirectional communication network between the nervous, immune, and vascular systems. This review systematically examines the pivotal role of this axis in maintaining cardiovascular homeostasis and in the pathogenesis of cardiovascular diseases. We first provide an overview of the fundamental signaling pathways between the components of this axis. Subsequently, we delve into the specific crosstalk mechanisms within the axis in the context of major cardiovascular conditions, including atherosclerosis, hypertension, and heart failure. A central focus is placed on critically evaluating the potential therapeutic targets and intervention strategies that have emerged from our understanding of this axis’s mechanisms. This review aims to provide a comprehensive perspective for understanding the multi-system pathogenesis of cardiovascular diseases and for informing the development of novel therapeutic approaches. 1 Introduction The human heart, long perceived as a mere mechanical pump, can be profoundly and acutely broken by the mind. This is vividly exemplified by Takotsubo syndrome (TTS), often termed “broken heart syndrome,” a transient form of acute heart failure typically triggered by severe emotional or psychological stress, such as the grief of loss, intense fear, or overwhelming anxiety (1). The condition predominantly affects postmenopausal women and presents with symptoms mimicking an acute coronary syndrome, including chest pain and electrocardiographic changes, but in the absence of obstructive coronary artery disease (2). The COVID-19 pandemic provided a stark, real-world illustration of this mind-heart connection, where the profound psychological stressors of social isolation, fear of infection, and societal upheaval led to a documented surge in TTS cases, even among individuals without evidence of SARS-CoV-2 infection itself (3). This phenomenon underscores that emotional distress can be directly transduced into myocardial injury, challenging the traditional cardiocentric view of heart disease. The pathophysiology of TTS is thought to involve a catecholamine storm, where a massive sympathetic nervous system (SNS) outflow in response to stress leads to excessive epinephrine and norepinephrine release, causing direct myocardial stunning and microvascular dysfunction (1). This clinical narrative serves as a compelling entry point into a far more extensive and intricate biological dialogue, revealing that the heart does not operate in isolation but is a central participant in a continuous, multidirectional conversation orchestrated by the brain and mediated by the immune system. This narrative challenges the conventional paradigm of cardiovascular disease (CVD) research, which has historically focused on local vascular pathology, lipid metabolism, and hemodynamic forces, often overlooking the brain as the central controller and the immune system as a critical effector. CVD remains the leading cause of global mortality, and while traditional risk factors like hypertension and dyslipidemia are well-established, they do not fully account for disease susceptibility or progression. Accumulating evidence now compellingly demonstrates that the nervous and immune systems are indispensable actors in the initiation, progression, and complications of CVD (4). This recognition has given rise to the integrative concept of the “neuroimmune cardiovascular axis” (or neuroimmune-cardiovascular axis) (5). This axis represents a dynamic, bidirectional communication network where the central nervous system (CNS), through the autonomic nervous system (ANS) and neuroendocrine pathways, engages in real-time dialogue with the peripheral immune system and the cardiovascular system itself (6). It is not a simple linear pathway but a complex circuit involving afferent sensory nerves that relay signals from the heart and vessels to the brain, and efferent sympathetic and parasympathetic nerves that convey commands back to cardiovascular and immune tissues (7). This communication is facilitated by a rich language of mediators, including neurotransmitters (e.g., norepinephrine, acetylcholine), neuropeptides (e.g., neuropeptide Y, substance P), cytokines, chemokines, and hormones, which collectively fine-tune vascular tone, immune surveillance, and tissue repair under physiological conditions (8). In pathological states, however, this finely tuned axis becomes dysregulated, driving cardiovascular pathogenesis. Chronic psychosocial stressors, such as social isolation or loneliness, can lead to sustained activation of the SNS and the hypothalamic-pituitary-adrenal (HPA) axis, creating a state of chronic low-grade inflammation and oxidative stress that accelerates atherosclerosis (9). This neuroimmune dysregulation is a central mechanism in hypertension, where immune cell infiltration into the vessel wall, kidney, and key cardiovascular regulatory centers in the brain contributes to increased vascular resistance and sympathetic tone (10). For instance, activated T cells and macrophages release pro-inflammatory cytokines like interleukin-6 (IL-6), interleukin-17 (IL-17), and tumor necrosis factor-alpha (TNF-α), which promote endothelial dysfunction, oxidative stress, and vascular remodeling (11). Conversely, signals from diseased cardiovascular tissues feed back to the CNS. In atherosclerosis, specialized “neuroimmune cardiovascular interfaces” (NICIs) form in the adventitia of diseased arteries, where expanded axon networks interact closely with immune cells (12). These NICIs are part of a structural “artery-brain circuit” (ABC), where nociceptive afferents from the arterial adventitia project to the spinal cord and higher brain regions like the amygdala, while sympathetic efferents from the brainstem and hypothalamus project back to the adventitia via ganglia (12). Activation of this circuit, including increased splenic sympathetic nerve activity, can exacerbate disease progression, while its therapeutic disruption attenuates atherosclerosis (12). Similarly, after stroke, neuroinflammation driven by activated microglia disrupts cardiovascular-related neural networks and the blood-brain barrier, allowing central immune components to influence peripheral immunity, leading to splenic activation and subsequent myocardial infiltration by monocytes, causing cardiovascular dysfunction (13). This evidence firmly establishes that the neuroimmune cardiovascular axis is a fundamental regulatory layer whose disruption is a critical driver of major cardiovascular conditions, from hypertension and atherosclerosis to myocardial infarction and heart failure. 2 Core components and fundamental communication mechanisms of the neural-immune-caridiovascular axis 2.1 Neural and neuroendocrine output pathways The nervous system exerts profound control over cardiovascular and immune functions through its efferent outputs, primarily mediated by the autonomic and sensory nervous systems. The sympathetic nervous system (SNS) plays a dominant role in this regulation. Sympathetic nerve terminals release norepinephrine (NE), which acts on specific adrenergic receptor subtypes expressed on distinct cell populations. On macrophages, NE primarily engages β2-adrenergic receptors (β2-AR) to modulate cytokine production—suppressing TNF-α and IL-12 while enhancing IL-10 at low concentrations, but paradoxically promoting pro-inflammatory cytokine release under conditions of chronic sympathetic overstimulation. On vascular smooth muscle cells (VSMCs), NE activates α1-adrenergic receptors (α1-AR) to drive vasoconstriction and proliferation, while β2-AR stimulation promotes VSMC relaxation and inhibits migration—a dichotomy that highlights the receptor-dependent pleiotropy of sympathetic signaling. On lymphocytes, β2-AR signaling suppresses Th1 responses while promoting Th2 and Th17 polarization, depending on the local cytokine milieu. On endothelial cells, NE acts through α2-AR to modulate NO release and endothelial permeability. This cell-type- and receptor-specific signaling architecture underpins the context-dependent effects of sympathetic activation in cardiovascular disease (14). This direct signaling modulates immune cell functions, including the secretion of pro-inflammatory cytokines, and induces vasoconstriction, thereby influencing blood flow and pressure (15). Chronic elevation in sympathetic tone is a well-established core pathway linking psychological stress to increased cardiovascular risk, as it perpetuates a state of inflammation and vascular dysregulation (16). In contrast, the parasympathetic nervous system, particularly through the vagus nerve, provides a critical counterbalance via the cholinergic anti-inflammatory pathway. Vagus nerve stimulation leads to the release of acetylcholine (ACh), which binds to the α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages, suppressing NF-κB activation and downstream pro-inflammatory cytokine production through the JAK2/STAT3 pathway. Beyond macrophages, α7nAChR is also expressed on T lymphocytes (where it modulates T-cell proliferation and cytokine secretion), dendritic cells (where it affects antigen presentation capacity), and endothelial cells (where it promotes NO production and maintains vascular barrier function). On VSMCs, ACh acts through muscarinic M3 receptors (M3R) to induce vasodilation via endothelium-dependent mechanisms, while M2 receptors on cardiac myocytes mediate parasympathetic control of heart rate. This receptor-specific cholinergic signaling establishes a multi-cellular anti-inflammatory and cardioprotective network that extends well beyond the canonical macrophage-centric model (14, 17). This interaction inhibits key pro-inflammatory signaling pathways, such as NF-κB activation, thereby suppressing the release of cytokines like TNF-α and IL-1β and exerting both local and systemic anti-inflammatory effects (18). This pathway is crucial for modulating the immune response in conditions such as sepsis and cardiovascular disease (19). Sensory neurons, which express channels like the transient receptor potential vanilloid 1 (TRPV1), serve a bidirectional role. They are responsible for afferent signaling, transmitting nociceptive and inflammatory signals from the periphery (e.g., from the heart or vasculature) to the central nervous system via neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) (20). Conversely, these same sensory nerve terminals can release neuropeptides in the periphery, directly influencing vascular permeability, immune cell recruitment, and contributing to neurogenic inflammation (21, 22). This efferent function of sensory nerves establishes a local neuroimmune interface, where neuropeptides like CGRP can regulate adaptive immune responses, as seen in skin immunity (23). Thus, the integrated output from autonomic and sensory nerves forms a dynamic network that continuously adjusts immune activity and vascular tone, with imbalances in this neural regulation being central to the pathogenesis of inflammatory cardiovascular diseases, hypertension, and heart failure (24, 25). Beyond the autonomic nervous system, the hypothalamic-pituitary-adrenal (HPA) axis represents another critical neuroendocrine output pathway that modulates immune function and cardiovascular homeostasis. Activation of the HPA axis in response to stress leads to the release of corticotropin-releasing hormone (CRH) from the hypothalamus, which stimulates pituitary adrenocorticotropic hormone (ACTH) secretion, ultimately driving adrenal glucocorticoid (primarily cortisol in humans) production. Glucocorticoids exert broad immunomodulatory effects by suppressing pro-inflammatory cytokine production, inhibiting NF-κB signaling, and promoting anti-inflammatory responses in innate and adaptive immune cells. In the cardiovascular system, chronic HPA axis dysregulation—characterized by sustained cortisol elevation—contributes to endothelial dysfunction, hypertension, and atherosclerosis progression. Importantly, glucocorticoids modulate the synthesis and release of catecholamines, establishing a bidirectional interaction between the HPA axis and sympathetic nervous system that amplifies neuroimmune signaling in CVD. Thus, the HPA axis functions as an indispensable humoral arm of the neuroimmune cardiovascular axis, translating psychosocial stress into sustained inflammatory and vascular pathology (26, 27). 2.2 Immune system response and signal feedback The immune system is not merely a passive target of neural signals but an active participant in a bidirectional dialogue with the nervous system, capable of both receiving and generating feedback. A fundamental basis for this crosstalk is the widespread expression of receptors for neurotransmitters and neuropeptides on immune cells. Myeloid cells, including monocytes, macrophages, and dendritic cells, as well as lymphocytes such as T cells and B cells, express a variety of receptors including adrenergic receptors, cholinergic receptors, and receptors for neuropeptides like neuropeptide Y (25, 28). This allows them to directly “sense” and respond to neural output, adjusting their functional state—for instance, shifting from a pro-inflammatory to an anti-inflammatory phenotype—based on the local neurochemical milieu (14). Furthermore, activated immune cells themselves become potent sources of signaling molecules. They produce a plethora of cytokines (e.g., TNF-α, IL-1β, IL-6), chemokines, and reactive oxygen species (10). The actions of these cytokines are determined by specific receptor engagement on target cells: TNF-α signals through TNFR1 (ubiquitously expressed, mediating apoptosis and inflammation) and TNFR2 (predominantly on immune cells, mediating survival and proliferation); IL-1β engages the IL-1 receptor type 1 (IL-1R1) on endothelial cells, VSMCs, and cardiac myocytes to activate NF-κB and MAPK pathways; IL-6 signals through either classical cis-signaling (membrane-bound IL-6R, predominantly on hepatocytes and immune cells) or trans-signaling (soluble IL-6R, affecting all cell types, including endothelial cells and VSMCs)—the latter being particularly pathogenic in cardiovascular disease. These mediators have dual effects: they directly affect the function of neighboring vascular cells, such as endothelial cells and smooth muscle cells, and they can act on peripheral nerve endings or, via circulation, influence the central nervous system (29). This feedback can alter neural output, creating regulatory loops. For example, pro-inflammatory cytokines can sensitize sensory neurons, lowering their activation threshold and contributing to pain and dysautonomia, while also influencing central autonomic centers to increase sympathetic drive (30). The spleen emerges as a critical peripheral organ where this neuroimmune integration is particularly dense and functionally significant. It receives rich sympathetic noradrenergic innervation and houses a large reservoir of immune cells (31). Sympathetic nerves within the spleen can directly modulate the distribution, trafficking, and function of lymphocyte subsets, thereby exerting a systemic influence on inflammatory processes central to diseases like atherosclerosis and hypertension (32, 33). Studies show that splenic sympathetic activation can promote a pro-inflammatory immune profile, contributing to cardiovascular disease progression (31). Conversely, the spleen also contains specialized glial cells that ensheath sympathetic axons and are transcriptionally poised for immune communication, further highlighting its role as a neuroimmune hub (33). This intricate feedback system ensures that immune responses are finely tuned and context-dependent, but its dysregulation—characterized by chronic immune activation and impaired neural feedback—is a hallmark of numerous cardiovascular pathologies, from myocardial infarction to heart failure, where it exacerbates tissue damage and remodeling (25, 34). In addition to innate immune cells, the adaptive immune system—particularly CD4+ T lymphocytes—plays an indispensable role in cardiovascular neuroimmunity (10, 11). T helper 1 (Th1) cells produce interferon-gamma (IFN-γ) and promote macrophage activation, while Th17 cells secrete interleukin-17 (IL-17) and drive neutrophilic inflammation; both subsets have been implicated in hypertension and atherosclerosis progression (35). Conversely, regulatory T cells (Tregs) exert immunosuppressive and atheroprotective functions by limiting excessive inflammation and maintaining immune tolerance (36). The sympathetic nervous system modulates this adaptive immune landscape through β2-adrenergic receptor signaling on T cells, which can suppress Th1 responses while promoting Th2 and Th17 polarization under certain contexts (14, 25). B cells also contribute to cardiovascular pathology through antibody production, antigen presentation, and cytokine secretion, with their function modulated by autonomic inputs (37). Thus, the adaptive immune system serves as both a sensor and effector of neural signals, translating sympathetic and parasympathetic tone into antigen-specific inflammatory or regulatory responses within the cardiovascular system. 2.3 Vascular system: the integrative and effector platform The vascular system serves as the primary effector and integrative platform where neural and immune signals converge to regulate hemodynamics, permeability, and inflammatory respon
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