Researchers Daniel E. Leisman, Matthijs Kox, and Peter Pickkers have proposed the concept of the vasopressor-immune gradient, a hypothesis highlighting that vasoactive medications currently used in clinical practice exert differential immunomodulatory effects in septic shock. Septic shock arises from a dysregulated host response whose manifestations range across a spectrum from acute hyperinflammation to profound immunosuppression, both of which contribute to poor patient outcomes. While catecholamines have long been administered exogenously to elevate blood pressure and are also released endogenously during acute physiologic stress, they represent often-overlooked contributors to sepsis-associated immunosuppression. Although extensive literature demonstrates the immunosuppressive actions of norepinephrine, the established first-line vasopressor for septic shock, alternative agents are clinically available. Emerging evidence indicates that these distinct vasoactive therapies alter immune function along a biological gradient, spanning from the broadly immunosuppressive actions of catecholamines at one extreme to the immunostimulatory effects of angiotensin-II at the other.
The immunosuppressive effects of catecholamines are well established experimentally, operating primarily through adrenergic signaling pathways. Nearly all immune cells express beta-adrenergic receptors, particularly the beta-2 receptor subtype. Signaling through beta-2 receptors elevates intracellular cyclic adenosine monophosphate and inhibits the nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells. In experimental infusion studies, exposure to epinephrine and norepinephrine leads to reduced pro-inflammatory cytokine release, impaired phagocytosis, and diminished formation of reactive oxygen species. Concurrently, catecholamine administration increases the release of anti-inflammatory interleukin-10 and promotes endotoxin tolerance. In addition to these beta-2 mediated pathways, researchers have also described a distinct, beta-1-mediated contribution that drives lymphocyte dysfunction.
Evidence detailing catecholamine-mediated immunosuppression remains predominantly experimental, supported by both controlled human models and animal investigations alongside clinical observations. In healthy human volunteers subjected to experimental endotoxin administration, an infusion of low-dose norepinephrine increased anti-inflammatory interleukin-10 concentrations while decreasing pro-inflammatory cytokines. In a clinical observational cohort comprising 195 patients with septic shock, higher doses of norepinephrine correlated with a lower blood ratio of tumor necrosis factor to interleukin-10, an association indicative of a more immunosuppressive phenotype that was attenuated among patients chronically receiving beta-blockers. Furthermore, in an abdominal sepsis model where mice underwent cecal ligation and puncture, norepinephrine administration increased bacterial dissemination to remote organs. Together, these laboratory and observational findings suggest catecholamines are a potentially modifiable factor in sepsis-associated immunosuppression, although future studies must evaluate whether alternative vasopressor selection can alter patient clinical outcomes.
In contrast to catecholamines, available evidence indicates that vasopressin has fewer direct effects on immune cell function. When tested across the same experimental models used to evaluate norepinephrine, vasopressin exerted no measurable effects on cytokine production, neutrophil reactive oxygen species formation, or bacterial dissemination. Investigators note that vasopressin may still indirectly influence immune activity by reducing patient exposure to catecholamines or by elevating cortisol levels. In the VASST clinical trial, certain circulating cytokines decreased among patients receiving vasopressin; however, these differences did not persist after statistical adjustment for baseline patient characteristics, and patients in the vasopressin arm also received lower overall doses of norepinephrine.
Positioned at the opposite end of the proposed gradient, angiotensin-II acts as a peptide hormone of the renin-angiotensin system that exerts direct immune-enhancing effects. The majority of circulating leukocytes express renin-angiotensin system-related proteins, prominently including the type-1 angiotensin receptor. Through activation of this type-1 receptor, angiotensin-II stimulates the release of inflammatory cytokines from endothelial cells, promotes leukocyte activation, and facilitates leukocyte migration into tissues while restoring cellular responsiveness to endotoxin. Additionally, certain subsets of leukocytes can synthesize angiotensin-II endogenously, actively upregulating angiotensin-generating enzymes when exposed to bacterial stimuli.
The biological actions of angiotensin-II are supported primarily by experimental findings and indirect clinical associations. In a mouse model of infection, administration of angiotensin-II enhanced bacterial clearance from both the peritoneal cavity and the bloodstream, increased innate immune cell phagocytosis, and restored monocyte responsiveness following an endotoxin challenge. Confirming that these responses depend on direct immune signaling, selective genetic deletion of the type-1 receptor from myeloid-lineage leukocytes completely abrogated these protective effects. Experimental data also reveal dynamic temporal changes in cytokine profiles during angiotensin-II administration, characterized by an early surge in chemokines and pro-inflammatory cytokines, followed by subsequent suppression of both pro- and anti-inflammatory mediators. Clinically, evidence remains indirect: circulating leukocytes isolated from patients with sepsis display marked upregulation of genes associated with the suppression of angiotensin-II signaling, and patients carrying genetic polymorphisms that cause over-expression of these angiotensin-suppressing genes suffer from increased mortality in septic shock, establishing the rationale for forthcoming randomized trials comparing angiotensin-II against norepinephrine.
The authors emphasize several biological complexities and caveats that prevent the vasopressor-immune axis from functioning as a simple on-off switch. First, immunomodulatory outcomes are complex and likely vary across different immune cell types. Second, vasoactive agents exert direct effects on pathogens: many Gram-negative bacteria express catecholamine receptors, and exposure to high concentrations of catecholamines increases bacterial virulence, whereas no analogous bacterial receptors have been identified for vasopressin or angiotensin-II. Third, in experimental angiotensin-II models, it remains challenging to disentangle whether time-dependent changes in cytokine profiles represent direct immunologic signaling or secondary responses driven by earlier, accelerated bacterial clearance. Finally, hyperinflammation and immunosuppression are biologically interconnected in septic shock, as acute mediator production during hyperinflammation drives the cellular reprogramming that underpins subsequent immunosuppressive states; consequently, agents such as norepinephrine that temper acute hyperinflammation might theoretically attenuate downstream immunosuppression.
The concept of a vasopressor-immune gradient suggests that vasoactive therapy in septic shock could ultimately be personalized based on the heterogeneity of individual immune responses, though the authors emphasize that current evidence does not yet support tailoring drug selection to immune profiles in clinical practice. Drawing an analogy to the recent ImmunoSep trial, where hyperinflamed patients benefited from immunosuppressive intervention while immunosuppressed patients benefited from immunostimulation, future hemodynamic strategies might eventually target specific immunologic phenotypes. Any future trial must carefully account for the timing and biological substrate of the infection: patients exhibiting exuberant early inflammation from antibiotic-susceptible pathogens at sites with good drug penetration may benefit from the immune brake provided by catecholamines, whereas patients with compartmentalized, antibiotic-resistant infections or pronounced endotoxin tolerance might benefit from immune augmentation. While prospective trials remain necessary to evaluate clinical outcomes, this conceptual gradient reframes circulatory support in sepsis as a potential immunomodulatory intervention.
Subject of Research: The vasopressor-immune gradient and differential immunomodulatory effects of vasoactive medications in septic shock
Article Title: Vasopressors as immunomodulators: a hidden axis in septic shock
Article References: Leisman, D. E., Kox, M., & Pickkers, P. (2026). Vasopressors as immunomodulators: a hidden axis in septic shock. Intensive Care Medicine. https://doi.org/10.1007/s00134-026-08648-3
Image Credits: AI Generated
DOI: 10.1007/s00134-026-08648-3
Keywords: septic shock, vasopressors, norepinephrine, angiotensin-II, vasopressin, immunomodulation, catecholamines, intensive care medicine, immunomodulators, hidden, axis, septic
Tags: angiotensin IIaxiscatecholamineshiddenimmunomodulationimmunomodulatorsintensive care medicinenorepinephrinesepticseptic shockvasopressinvasopressors
