When a pathogen invades the body, it can cause significant harm on its own. But just as often, the real destruction may come from the body’s own defenses. This is the case for periodontal disease, also known as gum disease, since it refers to the inflammation of the gums that surround teeth. Periodontal disease often starts with the growth of sticky films of bacteria that later lead to chronic gum inflammation, bone loss, and sometimes tooth loss.
A new therapy delivering a protein that modulates the host’s local immune response could help treat this condition, according to a recent study. Researchers led by Charles Sfeir at the University of Pittsburgh School of Dental Medicine reported that injecting microparticles loaded with this immunomodulator into a mouse model of periodontal disease inhibited bone loss and accelerated repair at different stages of the disease (1).
While current interventions like dental deep cleaning, antibiotics, and surgery can help patients with periodontal disease, they come with limitations. For example, recurrent antibiotic use may contribute to the development of antibiotic resistance. “It’s not like you can give someone antibiotics chronically for the rest of their life to treat periodontal disease,” said Yvonne Hernandez-Kapila, a clinician scientist at the University of California, Los Angeles, who did not participate in the new work. Due to these limitations and the variability in patient responses to treatments, there’s always the need to look for alternative therapies, she added.
It’s not like you can give someone antibiotics chronically for the rest of their life to treat periodontal disease.
- Yvonne Hernandez-Kapila, University of California, Los Angeles
Unlike most existing gum disease interventions that primarily target the bacteria causing the condition, Sfeir and his team focused on modulating the immune response, which is key in the development of periodontal disease. They engineered microparticles containing C-C motif chemokine ligand 2 (CCL2), a protein that under certain conditions induces a macrophage response that promotes inflammation resolution and tissue repair (2,3). These microparticles are encapsulated in a degradable polymer, enabling a gradual and sustained release of CCL2 over at least 30 days following delivery.
Then, the team induced periodontal disease in mice by placing a silk ligature around a tooth to promote plaque biofilm accumulation. To test the therapy’s effect as a preventive, interventional, or reparative approach, respectively, they injected mice with CCL2 microparticles at one of three stages: the day of the ligature placement, four days later, or the day of ligature removal. The therapy reduced bone loss by 32 to 37 percent in the preventive procedure and 26 to 29 percent in the interventional group, compared to control mice (which were not treated at all, or treated with microparticles without CCL2). Mice that received CCL2 after the removal of the ligature recovered up to 56 percent of bone, compared to 17 to 30 percent in the control groups.
These effects mostly resulted from CCL2’s ability to promote an anti-inflammatory phenotype in macrophages. Specifically, single-cell RNA sequencing analyses of immune cells in the gums of treated mice revealed that CCL2 therapy inhibited the triggering receptor expressed on myeloid cells-1 (TREM-1), which induces periodontal inflammation, while activating protein kinase A (PKA), involved in inflammation resolution (4,5). Furthermore, CCL2 indirectly affected bacterial presence around the tooth, reducing bacterial load in the area, likely by decreasing nutrients derived from tissue destruction.
Hernandez-Kapila said that Sfeir and his team showed strong evidence that CCL2 microparticles prevented bone loss in this ligature-induced periodontal disease mouse model. Yet, “[this] is a very acute and aggressive model of the disease,” she said, indicating that the model doesn’t accurately represent the condition’s chronic nature. “No model is perfect,” she acknowledged, and stressed the importance of testing the therapy in other periodontal disease animal models before translating it to humans. She also highlighted the need to assess any potential toxic effects of the drug — for example, by looking at the livers and kidneys of treated mice. Despite the local delivery, she noted, it’s unclear whether the agent could be incorporated into the bloodstream, especially given that leaky gums are a hallmark of periodontal disease.
Sfeir said that his team has tested the therapy in another mouse model and in dogs, but those results have not yet been published. Regarding toxicity, he explained that since the microparticles’ content is released at the nanogram level, it will be difficult to detect it in tissues. “What we did very early on was to feed the mice milligram levels of microparticles, and we did not observe any toxicity,” he said. As the team prepares for a Food and Drug Administration (FDA) submission, Sfeir noted that they will likely perform these toxicity studies under specific guidelines. “We are not expecting to see any toxicity because of the small amounts released,” he said.
Overall, the results so far are exciting, Hernandez-Kapila concluded. Since “it’s a new thing for us to test, it gives hope,” she said.
References
- Shehabeldin, M. et al. Therapeutic delivery of CCL2 modulates immune response and restores host–microbe homeostasis. Proc Natl Acad Sci 121, e2400528121 (2024).
- Wood, S. et al. Pro-Inflammatory Chemokine CCL2 (MCP-1) Promotes Healing in Diabetic Wounds by Restoring the Macrophage Response. PLoS One 9, e91574 (2014).
- Roca, H. et al. CCL2 and Interleukin-6 Promote Survival of Human CD11b+ Peripheral Blood Mononuclear Cells and Induce M2-type Macrophage Polarization. J Biol Chem 284, 34342-54 (2009).
- Wu, D. et al. Trem1 Induces Periodontal Inflammation via Regulating M1 Polarization. J Dent Res 101, 437-447 (2022).
- Kong, D. et al. PKA regulatory IIα subunit is essential for PGD2-mediated resolution of inflammation. J Exp Med 213, 2209-26 (2016).