Periodontitis aggravates pulmonary fibrosis by Porphyromonas gingivalis-promoted infiltration of neutrophils and Th17 cells

Hui-Lin Ye^1,2Xiao-Qian Meng^1,2Huxiao Li^2,3Wen-Zhen Lin²Lu-Jun Zhou²Jun Zhang²Chenchen Hou⁴Shuo Xu²Boyan Chen²Che Qiu^2,3Yu-Lin Li²Yong-Li Wang^2,5Li-Feng Yan⁴Sheng-Zhong Duan^1,2,5*

• ¹Department of Endodontics, Shanghai Ninth People’s Hospital, Shanghai, China
• ²Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
• ³Department of Periodontology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
• ⁴Department of Respiratory and Critical Care Medicine, Shanghai Ninth People’s Hospital, Shanghai, China
• ⁵Stomatology Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. However, the pathogeny of IPF is poorly understood, and therapeutic options are very limited. Periodontitis (PD) is a chronic inflammatory disease that leads to dysbiosis of both the oral microbiome and host immune responses. While previous studies have suggested a PD-IPF association, insights into the mechanisms remain limited. In this study, The PD mouse model was established by the ligation of molars and oral inoculation of subgingival plaques from PD patients and subsequently incorporated with a bleomycin-induced pulmonary fibrosis model. By the unbiased analysis using flow cytometry, PD is verified to significantly aggravate pulmonary fibrosis in mice via increasing the infiltration of neutrophils and Th17 cells. Th17 cells regulate neutrophils via IL-17A in PD-induced aggravation of pulmonary fibrosis. The PD pathogen Porphyromonas gingivalis (Pg) is detected enriched in both the oral cavity and lungs using 16S rRNA gene sequencing and fluorescence in situ hybridization. Pg is further determined to exacerbate pulmonary fibrosis by increasing the recruitment of neutrophils and Th17 cells. Overall, this study demonstrates that PD aggravates pulmonary fibrosis in mice, which is likely induced by Pg-promoted infiltration of neutrophils and Th17 cells. Treatment targeting PD or Pg might be a promising strategy to clinically ameliorate IPF.