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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE274721 | GEO | 2024/08/14

REPOSITORIES: GEO

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Project description:Oral health is associated with a symbiotic microbial community and host-microbe homeostasis is maintained by the controlled immune response. Various factors can disrupt this homeostasis. Dysbiosis, which is characterized by increased immune response and a shift in the microbiome, contributes the pathogenesis of peri-implantitis. Peri-implant mucosa and commensal bacteria play important roles in the maintenance of host-microbe homeostasis, but little is known about how they interact. We have therefore investigated the early host-microbe interaction between a commensal multispecies biofilm (Streptococcus oralis, Actinomyces naeslundii, Veillonella dispar, Porphyromonas gingivalis) and peri-implant mucosa at 24 and 48 h. Our in vitro peri-implant mucosa-biofilm model contained organotypic oral mucosa, implant material and biofilm. After 24 h, the biofilm induced a modest innate immune response in the peri-implant mucosa by the upregulation of 5 genes related to immune and inflammatory response and the increased secretion of IL-6 and CCL20. This controlled immune response protected tissue integrity and the peri-implant mucosa remained intact. The secreted antibacterial proteins human β-Defensins-1, -2, and CCL20 controlled the overgrowth of the biofilm by reducing its volume - without affecting the live/dead ratio or bacterial distribution. Thus, host-microbe homeostasis was established within the first 24 h. In contrast, host-microbe homeostasis was disrupted after 48 h. The mucosa was damaged and detached from the implant, due to the induced downregulation of cell adhesion related genes. The immune response was enhanced by upregulation of additional genes related to the immune and inflammatory response and increased secretion of IL-1β, TNF-α, and CCL20. Moreover, bacterial distribution was altered, with an increased proportion of V. dispar. The disrupted host-microbe homeostasis could lead to incipient dysbiosis. This deeper understanding of the early host-microbe interaction at the peri-implant site may provide the basis for new strategies to improve the prevention and therapy of peri-implant diseases.

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

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