Therapeutic Delivery of CCL2 Modulates Immune Response and Restores Host-microbe Homeostasis

The oral cavity is an easily accessible environment that allows for protective interventions aiming at modulating the immune response to control disease processes driven by a breakdown of host- microbe homeostasis. Periodontal disease (PD) is a prevalent condition in which quantitative and qualitative changes of the oral microbiota (dysbiosis) trigger non-resolving chronic inflammation, progressive bone loss and ultimately tooth loss. Here, we demonstrate the therapeutic benefit of local sustained delivery of the myeloid-recruiting chemokine CCL2 in murine ligature-induced PD using clinically relevant models as a preventive, interventional or reparative therapy. Local delivery of CCL2 into the periodontium inhibited bone loss and accelerated bone gain that could be ascribed to reduced osteoclasts numbers. CCL2 treatment upregulated M2-macrophage and downregulated pro-inflammatory and pro-osteoclastic markers. Furthermore, single cell RNA sequencing indicated that CCL2 therapy reversed disease-associated transcriptomic profiles of murine gingival macrophages via inhibiting TREM-1 signaling in classically activated macrophages and inducing PKA signaling in infiltrating macrophages. Finally, 16S rRNA sequencing showed mitigation of microbial dysbiosis in the periodontium that correlated with a reduction in microbial load in CCL2- treated mice. This study reveals a novel protective effect of CCL2 local delivery in PD as a model for chronic inflammatory diseases caused by a disturbance in host-microbe homeostasis.