Immune cell β2-adrenergic receptor signaling in myocardial injury: from neuroimmune crosstalk to precision immunomodulation

The β2-adrenergic receptor (β2-AR), a G protein-coupled receptor widely expressed on immune cells, has emerged as an important regulator linking sympathetic activation with inflammatory responses during myocardial injury. Beyond its established cardiovascular functions, β2-AR orchestrates immune cell migration, polarization, cytokine production, and efferocytosis, thereby shaping the initiation, resolution, and repair phases of cardiac inflammation. Recent studies have identified several immune-specific mechanisms through which β2-AR regulates leukocyte trafficking via the VCAM-1 and CCR2 axes, influences Annexin A1-dependent efferocytosis, and undergoes functional reprogramming through GRK2- and β-arrestin-mediated signaling. These mechanisms highlight the dynamic and context-dependent nature of immune β2-AR signaling, while also helping to explain why therapeutic modulation of this pathway has shown inconsistent clinical efficacy despite encouraging experimental findings. Current therapeutic strategies include selective β-blockade and GRK2-targeted interventions, whereas emerging approaches such as immune cell-specific β2-AR restoration, βARKct gene delivery, and biomaterial-based pro-resolving therapies remain at the preclinical stage. This review summarizes the expression patterns, signaling mechanisms, and immunoregulatory functions of β2-AR in immune cells, discusses its context-dependent roles across myocardial infarction, ischemia/reperfusion injury, and heart failure, and highlights current translational challenges and future opportunities for precision immunomodulation targeting immune cell β2-AR signaling.