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Chemokines in Oral Inflammatory Diseases: Apical Periodontitis and Periodontal Disease
T.A. Silva1,*,
G.P. Garlet2,
S.Y. Fukada3,
J.S. Silva4 and
F.Q. Cunha3
1 Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, CEP 31.270-901, Belo Horizonte, Minas Gerais, Brazil;
2 Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, São Paulo, Brazil;
3 Departments of Pharmacology and
4 Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
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Figure 1. Chemokines and chemokine receptors in oral tissues: potential involvement in the induction and maintenance of inflammatory reactions. A schematic representation of chemokine and chemokine receptor networks in oral tissues. Chemokine expression can be triggered by microbial components, inflammatory mediators, host factors such as dentin proteins, or even by mechanical stress. Both resident (such as osteoblasts, fibroblasts, mast, epithelial, and endothelial cells) and inflammatory cells (polymorphonuclear leukocytes [PMNs], lymphocytes, monocytes/macrophages) can be sources of chemokines in the oral environment. The chemokines produced in oral tissues selectively attract different cell types to the tissues, such as PMNs, lymphocyte subsets, monocytes/macrophages, and osteoclasts, and, consequently, can determine the course of inflammatory reactions and the clinical outcome of potentially associated diseases.
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Figure 2. Chemokines and bone tissue. A schematic representation of chemokine networks in bone tissue, in which both osteoclasts and osteoblasts can be targets of chemokines. Chemokines such as MCP-1/CCL2, SDF-1 /CXCL12, MIP-1/CCL3, and MIP-1 /CCL9 can induce the chemotaxis and differentiation of osteoclast precursors into osteoclasts. Other chemokines, such as IL-8/CXCL1, MCP-3/CCL7, CKβ8/CCL23, and IP-10/CXCL10, also act in osteoclasts. However, the activation of osteoclasts is achieved only with RANKL, which also induces chemokine production, generating an amplification loop to potentiate bone resorption. Chemokines such as SDF-1/CXCL12, BCA-1/CXCL13, and RANTES/CCL5 act on osteoblast precursors, driving their proliferation and cell survival, chemotaxis, and the production of type-I collagen, which can result in increased bone formation. The osteoblasts are also an important source of chemokines, produced in response to a wide range of stimuli, such as microbial products, inflammatory mediators, or dentin proteins. While osteoblast-derived MCP-1/CCL2 and SDF-1/CXCL12 participate in an interesting chemokine cross-talk between osteoblasts and osteoclasts, chemokines such as LIX/CXCL5 and BCA-1/CXCL13 can also attract different leukocyte subsets, suggesting an important role for osteoblasts in the inflammatory-immune reaction.
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Figure 3. Chemokines in healthy and diseased periodontal tissues. A schematic representation of chemokine networks in periodontal tissues, in which the bacterial biofilm hosting periodontopathogens is thought to trigger the expression of chemokines and other inflammatory mediators in gingival tissues. In healthy conditions (left), a slight expression of IL-8/CXCL8 in junctional epithelium is correlated with the subclinical inflammatory infiltrate, composed basically of polymorphonuclear leukocytes (PMNs). In addition, 6Ckine/CCL21 expression in lymphatic vessels is exclusively found in healthy periodontal tissue. In contrast, in periodontitis tissues, an intense expression of several chemokines can be observed. An increased expression of IL-8/CXCL8 is found in junctional epithelium, and directs an intense PMN influx to these areas. In periodontal connective tissues, chemokines such as MCP-1/CCL2 and RANTES/CCL5 can drive the migration of macrophages, IP-10/CXCL10 and MIP-1/CCL3 are chemoattractants of Th1-type lymphocytes, and chemokines such as MDC/CCL22 and TCA-3/I-309/CCL1 can attract Th2-type lymphocytes. The accumulation of B-cells can be driven by BCA-1/CXCL13, while chemokines such as MIP-1/CCL3 and SDF-1/CXCL12 can also be involved in the migration and activation of osteoclasts, thereby contributing to disease severity.
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Figure 4. Pulpal and periapical scenarios orchestrated by chemokines. A schematic representation of periapical lesion formation, supported by an inflammatory and immune response against micro-organisms that invade and destroy the dental pulp. In inflamed pulp, the chemokines MIP-3/CCL20 (a CCR6 ligand), IL-8/CXCL-8, and MCP-1/CCL-2 expression contribute to inflammatory cell infiltration. The progression of pulpal inflammation to the periapex and colonization of the root canal system by micro-organisms leads to soft- and hard-tissue destruction. In the periapex, chemokine production, which can be invoked by micro-organisms, dentin proteins, and dental materials, supports migration of leukocyte subsets, lymphocytes, and bone cells. Gram-negative flora is able to induce the production of IL-8/CXCL8 by pulp fibroblasts, osteoblasts, and the production of MIP-1/CCL3 and MIP-1β/CCL4 by neutrophils. CXCR1 expression was detected in neutrophils, which are attracted by IL-8/CXCL8. Chemokines and receptors expressed in cysts and granulomas comprise, CCR1—expressed in monocytes/macrophages, lymphocytes and osteoclasts—and its ligands MIP-1/CCL3 and RANTES/CCL5. CCR2 and CCR5 are found in monocytes/macrophages and lymphocytes, and their ligands are MCP-1/CCL2 (CCR2), MIP-1/CCL3, MIP-1β/CCL4, and RANTES/CCL5 (CCR5 ligands). CXCR3 and CCR3 are expressed in lymphocytes, and their ligands are MCP-2/CCL8 (CCR3) and IP-10/CXCL10 (CXCR3). Chemokine expression in apical periodontitis contributes to persistent inflammatory cell infiltration and the chronicity of apical lesions.
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Journal of Dental Research, Vol. 86, No. 4,
306-319 (2007)
DOI: 10.1177/154405910708600403
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