UCHL1 Exacerbates Periodontitis by Coordinating Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Macrophages

BACKGROUND: Given the pivotal role of macrophages in both the progression and regenerative phases of periodontitis, targeting macrophage-mediated immunity represents a novel therapeutic strategy for periodontitis management. Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) has been previously implicated in inflammatory processes. However, how UCHL1 regulates macrophage immune response in periodontitis remains to be elucidated. METHODS: Ligature-induced periodontitis mice and Porphyromonas gingivalis lipopolysaccharide (P.g LPS) were used to investigate the expression of UCHL1 in macrophages during immune responses. Lentivirus and an inhibitor were conducted to determine the role of UCHL1 in the periodontitis-associated macrophage immune response. The mitochondrial function and the endoplasmic reticulum status of macrophages were examined to elucidate the underlying mechanisms. Finally, we constructed hydrogels containing UCHL1 inhibitor and evaluated their efficacy in treating periodontitis. RESULTS: The expression of UCHL1 was upregulated in proinflammatory immune response of periodontitis-associated macrophages. Inhibition of UCHL1 reduced the expression and release of TNF-α, IL-6, and IL-1β. In addition, inhibition of UCHL1 in macrophages improved the osteogenesis and migration ability of MC3T3-E1 cells in the co-culture system. Mechanistically, inhibition of UCHL1 ameliorated LPS-induced mitochondrial damage and endoplasmic reticulum stress in macrophages. LDN@GelMA hydrogel had great in vitro anti-inflammatory and bone-promoting effects. Periodontal injection of LDN@GelMA hydrogel alleviated local inflammation and promoted alveolar bone regeneration. CONCLUSIONS: Our data suggest that UCHL1 may serve as a critical negative regulator for periodontitis treatment, and inhibition of UCHL1 is expected to improve the periodontal inflammatory microenvironment and promote alveolar bone regeneration.