Therapeutic delivery of CCL2 modulates immune response and restores host-microbe homeostasis

• 成果类型: Article
• 署名作者: Shehabeldin, Mostafa; Gao, Jin; Cho, Yejin; Chong, Rong; Tabib, Tracy; Li, Lu; Smardz, Matthew; Gaffen, Sarah L.; Diaz, Patricia I.; Lafyatis, Robert; Little, Steven R.; Sfeir, Charles
• 署名单位: Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; State University of New York (SUNY) System; University at Buffalo, SUNY; SUNY Delhi; State University of New York (SUNY) System; University at Buffalo, SUNY; SUNY Delhi; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13016
• DOI: 10.1073/pnas.2400528121
• 发表日期: 2024-09-03
• 关键词: myeloid cells 1; osteoclast differentiation; resolvin e1; periodontal-disease; bone loss; receptor; inflammation; murine; RECRUITMENT; expression

摘要

Many chronic inflammatory diseases are attributed to disturbances in host-microbe interactions, which drive immune- mediated tissue damage. Depending on the anatomic setting, a chronic inflammatory disease can exert unique local and systemic influences, which provide an exceptional opportunity for understanding disease mechanism and testing therapeutic interventions. 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 nonresolving chronic inflammation, progressive bone loss, and ultimately tooth loss. Here, we demonstrate the therapeutic benefit of local sustained delivery of the 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 up- regulated M2- macrophage and downregulated proinflammatory and pro- osteoclastic markers. Furthermore, single- cell ribonucleic acid (RNA) sequencing indicated that CCL2 therapy reversed disease- associated transcriptomic profiles of murine gingival macrophages via inhibiting the triggering receptor expressed on myeloid cells- 1 (TREM- 1) signaling in classically activated macrophages and inducing protein kinase A (PKA) signaling in infilmitigation 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.