Periodontitis (PD) is a prevalent chronic inflammatory disorder that is associated with alveolar bone loss and systemic diseases[1]. Despite the self-healing capacity of bone tissue, bone loss in PD is largely irreversible. Existing strategies for bone regeneration, such as biomaterials, have had limited success in PD[2]. The aberrant host osteoimmunity to pathogenic bacteria is responsible for the destruction of alveolar bone in PD[3]. Therefore, investigating the distinctive activity of immune cells in PD is essential to create more effective and precise therapeutic approaches for treating PD.

Neutrophils are a key type immune cell in bones that aggravate alveolar bone loss[4]. Bacterial infection causes the release of various chemokines, such as G-CSF, CXCL2, and CXCL8, thereby recruiting circulating neutrophils to inflamed sites in alveolar bone[5]. Abnormal neutrophil function aggravates alveolar bone loss by increasing reactive oxygen species (ROS) production and neutrophil extracellular trap (NET) release[6]. Neutrophils are classified into the following two subtypes based on their response to stimulation: N1, the high-responder, is pro-inflammatory and has strong migratory abilities; and N2, the low-responder, is anti-inflammatory[7], [8]. High-responder neutrophils have higher expression in chronic PD patients than in healthy individuals, leading to increased oxidative burst[9], [10], [11], [12]. However, the exact function of these cells in PD and whether targeting abnormal molecules in these cells can reduced alveolar bone loss remain unclear.

Single-cell RNA sequencing (scRNA-seq) enables us to specifically profile cell populations and gene expression at the single-cell level, thereby revealing the different functions of immune cells in various diseases[13]. As previous studies have reported human single-cell atlases for PD[14], we integrated these data and compared neutrophil function between PD and healthy individuals at single-cell resolution. Furthermore, both PD and chronic apical periodontitis (CAP) can lead to alveolar bone loss, yet the healing of alveolar bone is more successful in CAP than in PD[15], [16], [17], [18]. Whether the differences in neutrophil's function between PD and CAP are responsible for the varying healing efficacy of alveolar bone remains unclear. Investigating the differences in the response of neutrophils in PD and CAP could be beneficial for developing more effective treatments for alveolar bone loss caused by these two diseases.

In this study, we aimed to target dysfunctional neutrophils of PD to explore more precise strategies for this disease. We revealed that neutrophils expressed higher levels of CXCR1/2 and had a stronger pro-inflammatory capacity and chemotactic ability in the inflamed alveolar bone of PD patients. Suppressing the recruitment of neutrophils to inflamed sites with the CXCR1/2 inhibitor reparixin reduced alveolar bone loss in PD mice. This study sheds new light on the precise treatment of alveolar bone defects in PD.