Acta Pharmacol Sin. 2026 May 26. doi: 10.1038/s41401-026-01841-6. Online ahead of print.
ABSTRACT
Emerging evidence links cardiovascular disease (CVD) to organ-to-organ signaling that extends beyond the heart. The spleen is increasingly recognized as an innervated immune organ that rapidly remodels after cardiovascular injury and, in turn, regulates myocardial inflammation, repair, and remodeling. Human studies support clinical relevance through associations between splenic imaging phenotypes and cardiovascular risk or prognosis, while animal studies provide mechanistic support through spleen-targeted perturbations and mapping of immune trafficking and secreted mediators. This review synthesizes spleen-heart crosstalk as three interacting, bidirectional pathways including neural, immune, and secretory, and highlights phase dependence and spleen-specific mechanisms. The neural pathway links cardiac stress sensing and central autonomic processing to splenic sympathetic signals; for example, transcutaneous auricular vagus nerve stimulation (taVNS) activates a vago-splenic axis that reduces infarct size in patients with acute myocardial infarction. The immune pathway involves splenic leukocyte reservoirs, extramedullary hematopoiesis, and trafficking programs that may initially exhibit inflammatory characteristics following injury but transition to reparative roles during the resolution phase. This is exemplified by CCR2-dependent splenic monocyte egress, which influences infarct inflammation, and CD169⁺Tim4⁺ splenic macrophages, which facilitate wound healing. The secretory pathway comprises soluble mediators and extracellular vesicles (EVs) signaling that can instruct splenic responses and modulate cardiac target cells; specific examples include placental growth factor (PlGF) release from the spleen driving adaptive remodeling in pressure overload, and VCAM-1⁺ endothelial cell-derived EVs rapidly mobilizing neutrophils to the ischemic myocardium. Despite these advancements, significant knowledge gaps remain: the precise identification of splenic cellular sources for soluble mediators and EVs, the determination of recipient cardiac cell types and their functional interactions, and the mapping of phase-specific neural circuit dynamics across various CVD states. Translational priorities include the implementation of time-windowed targeting informed by spleen-state biomarkers (e.g., splenic FDG-PET activity, volume/stiffness), rigorous source-to-target validation through lineage-restricted perturbations, and the development of recipient-level engagement panels to facilitate mechanism-based, spleen-informed therapies for CVD.
PMID:42185683 | DOI:10.1038/s41401-026-01841-6