The spleen: a novel player in human blood pressure regulation

Preclinical studies have identified the spleen as a key effector in the neuro-immune axis, where sympathetic signaling induces T cell activation and migration into vascular target organs. These findings align with the concept of neuroimmune crosstalk, a sophisticated, bidirectional communication system involving the central nervous system (CNS), the autonomic nervous system (ANS), the immune system, and immune organs like spleen and bone marrow. As reviewed by Calvillo et al.[1], this crosstalk plays a role in the development and maintenance of arterial hypertension by promoting neuroinflammation, immune cell mobilization, and vascular dysfunction through cytokine and neuropeptide signaling. The disruption of splenic sympathetic innervation or the pharmacologically modulation of this axis can mitigate hypertensive end-organ damage in murine models, extending this paradigm to human physiology, though precise pathways, in particular through the involvement of placental growth factor (PlGF) [2,3]. While differences in immune organization between species might account for the more modest effects seen in humans, these findings suggest a preserved immunologic contribution to vascular regulation. HUMAN-CENTERED INSIGHTS INTO SPLENIC INFLUENCE The contribution Nardin et al.[4], entitled “Potential Role of the Spleen in the Development of Arterial Hypertension in Humans,” offers a human-centered perspective on the emerging role of immune-mediated mechanisms in blood pressure (BP) regulation. This single-blinded, retrospective case–control study compared patients who underwent elective splenectomy with matched controls who had cholecystectomy. By integrating detailed ambulatory blood pressure monitoring, microvascular imaging, and immunophenotyping, the authors investigated a long-speculated but previously untested hypothesis in humans. The study revealed that splenectomized individuals had significantly lower 24-h and daytime DBP, even though their overall BP values remained within the normotensive range. While these differences may not independently impact cardiovascular risk at a population level, they could signal early subclinical microvascular remodeling. Supporting this, splenectomy significantly altered the association between diastolic BP and wall cross-sectional area and capillary recruitment. This suggests that the spleen may modulate vascular reactivity or tone, possibly through neuroimmune signaling mechanisms linking sympathetic neural influences with immune cell activation and tissue-level inflammation. This is the first human study proposing a regulatory role for the spleen in BP control, reinforcing preclinical findings that position the spleen as a new hub for sympathetic-immune interactions, particularly in angiotensin II-induced hypertension. These interactions are part of a vicious cycle of neuroinflammation, where bone marrow-derived immune cells, microglia, and neuropeptides such as neuropeptide Y and substance P perpetuate central and peripheral inflammation, thereby leading to hypertension. The authors also observed elevated levels of CD3+/CD8+ T-cells among splenectomized patients, further strengthening the potential link between spleen-dependent immune modulation and vascular function [4]. THE SPLEEN'S ROLE IN OBESITY-RELATED HYPERTENSION The research indicates that splenomegaly is observed in a significant percentage of patients with obesity, particularly those with conditions like nonalcoholic fatty liver disease (NAFLD) or metabolic syndrome. In obesity, the spleen undergoes structural and functional changes, involving macrophages, T cell activation and altered cytokine secretion. These changes contribute to a shift in immune cell profiles, specifically a reduction in regulatory T cells (Tregs) and an increase in pro-inflammatory monocytes and CD8+ T cells, that promotes a systemic inflammatory state known to impair vascular function. In parallel, chronic activation of the sympathetic nervous system (SNS) in obesity stimulates the spleen via splenic nerve fibers, promoting the release of immune cells and pro-inflammatory cytokines such as IL-6 and TNF-α. This sympathetic–splenic axis has been shown in preclinical studies to drive immune-mediated vascular injury and renal inflammation, two critical contributors to elevated blood pressure. Critically, the spleen serves as a reservoir for T cells that, once activated, migrate to the vasculature and kidneys, promoting endothelial dysfunction, vascular remodeling, and sodium retention, all key mechanisms in hypertension. Collectively, these findings suggest that the spleen could be more than an immunologic bystander in obesity-related hypertension, possibly representing a dynamic effector organ in the neuroimmune network. This immunologic imbalance, marked by decreased anti-inflammatory regulation and heightened effector immune responses, can exacerbate systemic inflammation and promote vascular dysfunction, including impaired vasodilation, increased vascular stiffness, and endothelial injury. Furthermore, inflammatory infiltration into the kidneys may disrupt sodium handling and pressure natriuresis, key mechanisms involved in blood pressure regulation. As a result, the dysregulated splenic immune environment observed in obesity may act as a critical upstream driver of hypertension, linking metabolic dysfunction to cardiovascular disease through neuroimmune and inflammatory pathways [1]. FUTURE DIRECTIONS AND THERAPEUTIC POTENTIAL This work lays the foundation for larger, prospective, and mechanistically detailed investigations into how immune organs influence cardiovascular regulation [4]. Key questions remain: are these BP differences sustained at the long term? Do they ultimately affect cardiovascular outcomes? Can splenic pathways be therapeutically targeted without compromising immune function? Incorporating the neuroimmune crosstalk framework will be crucial for answering these questions, as it unifies neural, vascular, and immune mechanisms within a shared pathophysiological context. Moving forward, prospective studies incorporating longitudinal data, larger sample sizes, and advanced immune profiling, including regulatory T cell dynamics, cytokine levels, and PlGF quantification will be essential. These studies will determine whether the observed subtle changes in diastolic BP and vascular architecture translate into significant cardiovascular risk modulation. Such research could inform whether targeting splenic pathways might complement existing antihypertensive strategies, especially in resistant or inflammation-driven hypertension. Importantly, collaborative studies across hypertension, rheumatology, and immunology will provide the multidisciplinary lens needed to fully explore these complex connections. A PARADIGM SHIFT IN HYPERTENSION RESEARCH Nardin et al.[4] have made an important first step in human hypertension research by exploring the spleen's influence on blood pressure and microvascular health. Their findings, while preliminary, support the provocative hypothesis that the spleen actively participates in systemic vascular regulation. This shifts the traditional view of the spleen from merely an immune organ to a potential modulator of blood pressure regulation, possibly via sympathetic-immune interactions. This opens exciting new directions, particularly for patients with obesity and hypertension, where immune and sympathetic dysregulation are common. It also suggests new therapeutic possibilities, such as targeting splenic neuroimmune signaling, for treating resistant or inflammation-driven hypertension. As the field increasingly recognizes the immune system's role in cardiovascular disease, and as neuroimmune crosstalk gains recognition as a central player in this process, this study paves the way for future research and, perhaps, future therapeutic innovations. ACKNOWLEDGEMENTS None. Conflicts of interest There are no conflicts of interest.