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

Several immune-mediated diseases are attributed to disturbances in host-microbe interactions. In this study, we used periodontal disease (PD) as a model to study the protective effect of modulating macrophages response against inflammatory bone loss and microbial dysbiosis. We investigated the therapeutic effect of local sustained delivery of CCL2 chemokine in murine PD as a preventive, interventional and reparative therapy for ligature-induced periodontitis. We hypothesized that locally delivered CCL2 would alleviate disease phenotype by restoring periodontal macrophages homeostasis and reversing the inflammation-induced changes in the periodontal microbiome. In this regard, local delivery of CCL2 inhibited bone loss and accelerated bone gain along with reduction of osteoclasts numbers in histological sections. Furthermore, our data show that CCL2 treatment upregulated the expression of M2 macrophages markers and downregulated the expression of pro-inflammatory and pro-osteoclastic markers. Finally, we performed single cell RNA sequencing and microbiome analysis of gingival tissues from mice treated with CCL2. Our results indicated that CCL2 therapy reversed the disease associated transcriptomic changes of murine gingival macrophages and partially prevented microbiome dysbiosis. Our study reveals a previously undescribed protective effect of local sustained delivery CCL2 in chronic diseases where inflammatory bone loss is caused by disturbance of host-microbe homeostasis.