Cardiomyocyte-derived Reg3γ drives aging-related atrial fibrillation by activating macrophages via the gp130/JAK1/STAT3 pathway

Background While advanced age is the primary driver of atrial fibrillation (AF), the mechanisms linking cardiac senescence to AF propensity remain poorly understood, leaving a critical gap in precision medicine interventions. Regenerating islet-derived 3γ (Reg3γ), a C-type lectin predominantly known for gut mucosal immunity, has an undefined role in the pathophysiology of inflammaging-induced AF. Methods Reg3γ was identified as a candidate regulator of aging-related AF via RNA sequencing and bioinformatics. To investigate the role of Reg3γ in aging-related AF, we analyzed Olink proteomics data from the UK Biobank to assess circulating Reg3γ levels in older adults and their association with AF risk. A cardiomyocyte-specific Reg3γ knockout mouse model was established. Cardiac function and AF inducibility were assessed by echocardiography and programmed intracardiac stimulation. Results Both naturally aged rats and D-galactose induced aging mice exhibited significantly increased AF susceptibility. Histopathological analysis of senescent atria revealed pronounced fibrosis, myofibrillar disarray, and substantial macrophage infiltration (Figure 1A-1G). Western blotting and immunofluorescence staining showed that Reg3γ expression was significantly upregulated in atrial tissues of these aging models, with cardiomyocytes identified as the predominant source (Figure 1H-1K). In the UK Biobank cohort, circulating Reg3γ levels were significantly elevated in older adults compared with younger controls and were positively associated with the risk of incident AF (Figure 1L, 1M). Crucially, cardiomyocyte-specific deficiency of Reg3γ significantly attenuated atrial structural remodeling and AF inducibility in aging mice (Figure 2A-2F). Mechanistically, in vitro experiments demonstrated that Reg3γ recruits and activates macrophages by directly binding to gp130, thereby activating the downstream JAK1/STAT3 signaling pathway (Figure 2G-2K). RNA sequencing of recombinant Reg3γ-treated bone marrow-derived macrophages (BMDMs) revealed significant upregulation of CCL17, a well-established marker of M2 macrophage polarization (Figure 2L, 2M). Furthermore, siRNA-mediated knockdown of gp130 or STAT3 in BMDMs abrogated Reg3γ-induced CCL17 production. Conclusions We identify Reg3γ as a cardiomyocyte-derived factor that orchestrates macrophage infiltration and M2 polarization in the aging atria. Our study defines the Reg3γ–gp130/JAK1/STAT3–CCL17 axis as a critical driver of age-related atrial remodeling, highlighting Reg3γ as a promising biomarker and therapeutic target for preventing aging-associated AF.Figure 1Figure 2