Induction of M2 Macrophages Prevents Bone Loss in Murine Periodontitis Models

Abstract

Periodontitis is characterized by the progressive destruction of tooth-supporting alveolar bone, which is mainly caused by chronic inflammation in response to persistent bacterial insult. It has recently become clear that the pathogenesis of periodontitis is associated with a high ratio of proinflammatory M1 (classically activated) macrophages to anti-inflammatory M2 (alternatively activated). To decrease the inflammatory activity, we locally delivered the C-C motif chemokine ligand 2 (CCL2) using controlled-release microparticles (MPs). CCL2 is known to promote chemotaxis of M0 or M2 phenotype macrophages to the inflamed site and induce M2 phenotype polarization locally. Our in vitro data showed that CCL2 increased the number of M2 phenotype macrophages, decreased TNF-α secretion, and enhanced chemotaxis of RAW264.7 cells toward CCL2 MPs. Moreover, we induced periodontal disease in 2 animal models through inoculation of Porphyromonas gingivalis and ligature around the murine molar. Micro–computed tomography analysis showed significant reduction of alveolar bone loss in the CCL2 MP treatment group when compared with a blank MP group and a no-treatment periodontitis group in both models. Immunohistologic analysis showed a significant increase in the M2 phenotype subset and a decrease in the M1 phenotype subset in the CCL2 MP group of the P. gingivalis–induced model. Also, in both models, tartrate-resistant acidic phosphatase staining showed significantly fewer numbers of osteoclasts in the CCL2 MP group in alveolar bone area. Moreover, quantitative polymerase chain reaction results showed a significant increase in IL-1RA (interleukin 1 receptor antagonist) mRNA expression and a decrease in RANKL (receptor activator of nuclear factor kappa-Β ligand) mRNA expression in the CCL2 MP group in the ligature model. In summary, manipulation of endogenous M2 phenotype macrophages with CCL2 MPs decreased the M1 phenotype:M2 phenotype ratio and prevented alveolar bone loss in mouse periodontitis models. The delivery of CCL2 MPs provides a novel approach to treat periodontal disease.

Disruption of Monocyte and Macrophage Homeostasis in Periodontitis

“…Intervention strategies aiming at an active shift from M1 to M2 phenotype could be a conceptually plausible therapeutic strategy in periodontitis, as suggested in a murine periodontitis model in which polarization of an M2 response was induced locally using C-C motif chemokine ligand 2 (CCL2) with controlled-release microparticles (34). CCL2 induces polarization of M2 macrophages at the injury site and activates anti-inflammatory cascades (35).…”

Immunophenotypic quantification of M1 and M2 macrophage polarization in radicular cysts of primary and permanent teeth

“…It is important to know the dynamics of macrophage polarization during pathological and physiological processes, understanding the cytokines, chemokines related to these processes, so that these cells can be manipulated and modulated with the intention of favouring tissue repair. In this sense, several researchers have studied therapeutics possibilities for diseases such as cancer (Ostuni et al , Ruffell , Mantovani et al , Evrard et al ) and also in diseases and treatments related to the oral cavity (Zhang et al , Lee et al , Yang et al , Zhuang et al ).…”

Osteoimmunology: Inflammatory osteolysis and regeneration of the alveolar bone

“…As already stated, there are not only M1 macrophages releasing inflammatory mediators and catabolic enzymes that drive the inflammatory process; M2 macrophages produce TGF‐β, IL10 and other signalling molecules that resolve inflammation and support tissue regeneration (Brancato & Albina, ; Mosser & Edwards, ). For example, induction of M2 macrophages by local delivery of CCL2 prevents bone loss in murine periodontitis models (Zhuang et al., ). The switch from M1 into M2 macrophages is tightly controlled, for instance by the metabolic switch from glycolysis allowing fast energy mobilization to the citrate (Krebs) cycle (O'Neill, ).…”