Abstract: Objective To investigate the expression of neuregulin 4 (Nrg4) and its receptor ErbB4 in the gingival crevicular fluid (GCF) of patients with periodontitis and their effects on periodontal tissue inflammation and alveolar bone loss in rats with experimental periodontitis. Methods A total of 80 healthy subjects and periodontitis patients were enrolled and divided into four groups (n=20): a health group (group H), a periodontitis group (group G), a stage Ⅱ grade B periodontitis group (group P1) and a stage Ⅲ grade B periodontitis group (group P2). Their GCF was collected, and the levels of ErbB4 and Nrg4 were detected by ELISA. Primary bone marrow-derived macrophages (BMDMs) and dendritic cells (BMDCs) were isolated and stimulated in vitro with IFNγ+LPS, and the intracellular expression of EGFR, ErbB2, ErbB3, and ErbB4 mRNA was measured by qPCR. Bone marrow-derived M1 macrophages were treated with Nrg4, and cell viability was detected by CCK-8 assay. Cell apoptosis were detected by flow cytometry with Annexin V/PI. An in vivo experimental periodontitis model of rats was constructed. A total of 15 rats were randomly divided into three groups (n=3): a sham operation group (group S), a model group (group M) and a Nrg4 recombinant protein treatment group (group T). The rats were subjected to micro-CT imaging analysis, followed by H-E staining and pathological analysis. Results Compared with group H, the expression of ErbB4 in the GCF of patients at each stage of periodontitis significantly increased (P<0.05), but the expression of Nrg4 significantly decreased (P<0.05). Meanwhile, in vitro stimulation of BMDMs with IFNγ+LPS resulted in significant up-regulation of ErbB4 mRNA expression (P<0.01). After Nrg4 treatment, the viability of bone marrow-derived M1 macrophages were significantly reduced, while cell apoptosis remarkably increased (P<0.01). According to micro-CT imaging analysis, Nrg4 recombinant protein was effective in the treatment of periodontitis. Compared with group M, group T showed remarkable decreases in the distance between the cement-enamel junction and the alveolar bone (CEJ-ABC), and increases in bone mineral density (BMD) and bone/tissue volume (BV/TV) (P<0.01). There was no significant difference as to the above four parameters between group T and group S. Conclusions The levels of ErbB4 and Nrg4 in GCF can be used as potential markers of inflammation in patients with periodontitis. Nrg4 recombinant protein shows good therapeutic effects in the treatment of periodontitis in vivo.