**3. Neutrophils in oral health**

produced by bone marrow stromal cells (**Figure 1A**). G‐CSF regulates mature neutrophil release from the bone marrow by interfering with the CXCR4‐CXCL12 interaction [12]. In addi‐ tion, interleukin‐17 (IL‐17) endorses granulopoiesis and neutrophil release by upregulation of G‐CSF (**Figure 1**) [10]. IL‐17 builds on an interesting positive loop of neutrophil recruitment. For example, in chronic inflammation sites, neutrophils produce IL‐17 and can also attract

CCL2 chemokines, which are ligands for CCR6 and CCR2 chemokine receptors, respectively, on Th17 cells. This interaction maintains Th17 cells at inflammation sites. Therefore, Th17 cells

Circulating neutrophils can be quickly mobilized to infection or inflammation sites through a systematically controlled process known as the leukocyte adhesion cascade, which achieves neutrophil transmigration (**Figure 1B**) [15]. The process initiates when endothelial cells get activated and upregulated the expression of adhesion receptors such as E‐ and P‐selec‐ tins. Neutrophils recognize these selectins and begin rolling on endothelial cells. This roll‐ ing depends on transient interactions of selectins with glycoprotein ligands on neutrophils. Next, neutrophils get activated by chemokines, which induce a high affinity state in integrins, another group of adhesion receptors. Interaction of both selectins and integrins with their cor‐ responding ligands leads to slow neutrophils rolling followed by a firm adhesion that brings neutrophils to a full stop. Finally, neutrophils crawl on the endothelium and transmigrate into infection or inflammation sites. This last process is regulated mainly by β2 integrins. Integrins are heterodimeric receptors formed by a unique α (CD11) and a common β (CD18) subunit that interact with adhesion ligands such as intercellular adhesion molecule‐1 (ICAM‐1) and ICAM‐2 on endothelial cells (**Figure 1B**). This leukocyte adhesion cascade is positive regu‐ lated by tissue‐derived cytokines and by tissue‐derived chemokines. Cytokines control the expression of endothelial adhesion molecules and chemokines induce integrins to change conformation into a high affinity state [16]. Once neutrophils move into tissues, they follow chemoattractant gradients to reach infection or inflammation sites. Some chemoattractants for neutrophils are activated by complement components, such as the anaphylatoxin C5a, and bacterial components, such as formyl‐methionyl‐leucyl‐phenylalanine (fMLF). Recently, it has been discovered that the leukocyte adhesion cascade is also negatively regulated by endog‐ enous inhibitors such as Del‐1 (developmental endothelial locus‐1), pentraxin 3, and growth‐

Neutrophils are mostly cleared in tissues (**Figure 1C**) and possibly also in the bone mar‐ row (**Figure 1A**). In tissues, once neutrophils have completed their antimicrobial duty, they undergo apoptosis. Resident phagocytes, for instance, macrophages and dendritic cells, clear neutrophils locally. Phagocytosis of apoptotic neutrophils reprograms mac‐ rophages to initiate an anti‐inflammatory response, characterized by the synthesis of tumor growth factor (TGF)‐β and IL‐10, and by a reduction in IL‐23 synthesis (**Figure 1**) [18]. IL‐23 cytokine induces IL‐17 synthesis; thus, the reduced IL‐17 levels lead to less

secrete more IL‐17 and more neutrophils are recruited [14].

T lymphocytes (Th17 cells) [13]. Neutrophils also release CCL20 and

IL‐17‐producing CD4<sup>+</sup>

70 Role of Neutrophils in Disease Pathogenesis

differentiation factor 15 [17].

**2.3. Clearance**

**2.2. Trafficking**

Commonly, it is thought that microbes are harmful to our health. Contrary to this thought, there are plenty of microbes that harmoniously live within our bodies and form our micro‐ biota. Homeostasis between the host and its symbiotic microbiota is a key factor to under‐ stand and maintain our health [22, 23]. Nevertheless, we are constantly exposed to microbes not belonging to our microbiota through the things we touch, the food we eat, and the air we inhale. Fortunately, our innate immune system protects us from this constant threat. The oral cavity is a special place, where the microbiota is constantly changing. Yet, homeostatic mecha‐ nisms exist that keep the oral microbiota in balance with the immune system. Neutrophils are actively recruited into the gingival sulcus by an interleukin (IL)‐8 gradient continuously secreted by the junctional epithelium, as this tissue is in close contact with the oral biofilm bacterial community (**Figure 2**). Neutrophils are mostly responsible for ensuring periodontal health by keeping this biofilm at check [24]. However, during gingivitis a moderate inflam‐ matory response is generated. If this inflammation is not controlled, for example, in situations or poor oral hygiene, gingivitis can lead to periodontitis, a chronic inflammatory disease. In this condition, microbial pathogens cannot be eliminated or controlled by neutrophils. In response, more neutrophils are recruited to the periodontal tissue. Neutrophil accumulation, instead of protecting, favors periodontal tissue damage and even bone loss (**Figure 2**). Thus, a close balance between neutrophil function and microbe challenge must be maintained to ensure periodontal health.
