Fibromodulin Deletion Alleviates Periodontitis Through Complement-Dependent B Cell Activation

The extracellular matrix (ECM) is regarded as a highly dynamic partner of the immune system, while the dysregulated ECM-immune system reaction is directly related to the pathogenesis and progression of periodontitis. Fibromodulin (FMOD) is a multifunctional matricellular modulator in ECM and has been found to play critical roles in various inflammatory diseases. However, whether FMOD exhibits a pivotal role in periodontitis and acts as the key point connecting ECM and the immune system in periodontitis remains elusive. FMOD-KO mice were conducted to explore the role of FMOD in periodontitis, and IHC, qPCR, and Western blot were performed to detect the phenotype. The single-cell RNA sequencing was conducted to detect the underlying mechanism of fmod-mediated periodontitis We found that FMOD expression was up-regulated in the inflamed periodontal tissues isolated from both periodontitis patients and ligature-induced periodontitis mice, and most importantly, the increased expression level of FMOD was accompanied by the more serious periodontal tissue destruction. Then, by constructing FMOD-KO mice, we found that the depletion of FMOD alleviated the progression of periodontitis with reduced periodontal inflammation and alveolar bone loss. Moreover, the single-cell RNA sequencing analysis showed that FMOD deletion led to the complement-dependent B cell activation through complement factor H (CFH)/ complement component 3 (C3)/ complement receptor 2 (CR2) signaling Together, our results strongly suggest that FMOD may be a key regulator of the local immune microenvironment in periodontitis and a promising target for future clinical treatment.