Neutrophil N1 and N2 Subsets and Their Possible Association with Periodontitis: A Scoping Review

Abstract

Periodontitis is a chronic non-communicable disease caused by dysbiotic changes that affect the subgingival microbiota. During periodontitis, neutrophils play a central role in the initial recognition of bacteria, and their number increases with the appearance of the first signs of periodontal inflammation. Recent evidence has led to the proposition that neutrophils can also functionally polarize, determining selective activity patterns related to different diseases. Two well-defined neutrophil phenotypes have been described, the pro-inflammatory N1 subset and the suppressor N2 subset. To date, it has not been established whether these different neutrophil subtypes play a role in the pathogenesis of periodontitis. Thus, this scoping review aimed to determine whether there was evidence to suggest that the neutrophils present in periodontal tissues can be associated with certain phenotypes. The research question, population, concept, and context sought to identify original articles, in humans, that detected the presence of neutrophils in the periodontal tissues of people affected by periodontitis. Based on the search strategy, we found 3658 studies. After removing the papers with abstracts not related to the outcome measures and eligibility criteria, 16 articles were included for qualitative analysis. Several studies identified the presence of different neutrophil subsets, specifically, the naive, pro- and para-inflammatory, hyper-reactive and hyper-active, and high- and low-responder phenotypes. The existing evidence demonstrates the presence of pro-inflammatory, hyper-reactive and high-responder neutrophils in periodontal tissues affected with periodontitis. There is no evidence demonstrating the presence of the N1 or N2 phenotypes in periodontal tissues during periodontitis. However, the existence of pro-inflammatory phenotypes, which increase NETosis and degranulation, and increase the production of pro-inflammatory cytokines, could be suggestive of the N1 phenotypes.

The role of the CX3CL1/CX3CR1 axis as potential inflammatory biomarkers in subjects with periodontitis and rheumatoid arthritis: A systematic review

“…Once neutrophils arrive at gingival tissues and in the presence of critical bacteria or pathobionts, they polarize towards the N1 phenotype that secrete cytokines that allow macrophage differentiation towards an M1 phenotype that promotes microbiota dysbiosis, inflammation, and alveolar bone loss. CX3CL1 also acts on osteoclast precursor cells that migrate through the osteoblast layer 50–52 . Thus, CX3CL1 is a potent chemoattractant for preosteoclasts and causes osteoclastogenesis, destroying periodontal tissues 53 …”

“…CX3CL1 also acts on osteoclast precursor cells that migrate through the osteoblast layer. 50 , 51 , 52 Thus, CX3CL1 is a potent chemoattractant for preosteoclasts and causes osteoclastogenesis, destroying periodontal tissues. 53 …”

“…CX3CL1 also acts on osteoclast precursor cells that migrate through the osteoblast layer. [50][51][52] Thus, CX3CL1 is a potent chemoattractant for preosteoclasts and causes osteoclastogenesis, destroying periodontal tissues. 53 Regarding pharmacological agents targeting the CX3CL1/CX3CR1 axis in the pathogenesis of periodontitis, it has been shown that the therapeutic CX3CR1 antagonist called "F1" was able to inhibit leukocyte recruitment in a murine model of thioglycolate-induce periodontitis.…”

D-mannose alleviates chronic periodontitis in rats by regulating the functions of neutrophils

“…In our study, D-mannose suppressed neutrophil recruitment, activation, and pro-in ammatory phenotype in periodontitis rats in vivo and in vitro models. Since there are different neutrophil subsets [32,33], it is an interesting question whether D-mannose plays an important role in the transition between neutrophil subsets. Our study showed that D-mannose suppresses in ltration of neutrophils and in ammation activation in gingival tissue.…”

The double‐edged role of neutrophil heterogeneity in inflammatory diseases and cancers

“…Hypodense neutrophils and the ability to form NETs in peripheral blood and gastrointestinal tissues in patients with idiopathic inflammatory myopathy and vasculitis were greatly upregulated 228,229 . Neutrophil subpopulations also have fundamental effects on periodontal health regulation, as CD177 + neutrophils were recruited to gingival crevicular fluid in periodontitis preferentially 230–232 . Some researchers have identified specific neutrophil subsets, such as CD14 + Ly6G low neutrophils, that could secrete growth factors NGF and IGF‐1, thereby promoting neuronal survival 233,234 .…”