Neutrophils and periodontitis: From pathological mechanisms to therapeutic opportunities

Periodontitis (PD) is a prevalent inflammatory disease causing gingival destruction and alveolar bone loss. Neutrophils dominate periodontal lesions and, while essential for host defense, become pathogenic when dysregulated. Their hyperactivated antimicrobial functions-phagocytosis, oxidative burst, degranulation, and neutrophil extracellular trap (NET) formation-drive oxidative stress, protease release, and aberrant NETosis, leading to tissue and bone damage. Cytokines, chemokines, microbial virulence factors, and aging further shape neutrophil responses, but chronic overactivation remains central to disease progression. This review summarizes recent insights into neutrophil-mediated mechanisms in PD and discusses emerging immunopharmacological interventions. Direct approaches include inhibitors of integrins, chemokine receptors, elastase, matrix metalloproteinases, and peptidyl arginine deiminase 4, as well as NET-scavenging nanocapsules and mitochondrial ROS inhibitors. Indirect strategies aim to modulate cytokine signaling or disrupt neutrophil crosstalk with osteoclasts and T helper cells. Novel candidates such as specialized pro-resolving mediators, stem cell-derived extracellular vesicles, senolytics, and D-mannose show particular promise in preclinical studies. Collectively, neutrophils are increasingly recognized not only as pathological drivers of PD but also as promising therapeutic targets. A deeper understanding of neutrophil biology and immunomodulatory approaches may pave the way for innovative treatments in periodontitis and related inflammatory conditions.