Abstract
Periodontal disease is a prevalent chronic inflammatory condition characterised by an aberrant host response to a pathogenic plaque biofilm resulting in local tissue damage and frustrated healing that can result in tooth loss. Cysteine proteases (gingipains) from the key periodontal pathogen Porphyromonas gingivalis have been implicated in periodontal disease pathogenesis by inhibiting inflammation resolution and are linked with systemic chronic inflammatory conditions such as rheumatoid arthritis. Efficient clearance of apoptotic cells is essential for the resolution of inflammation and tissue restoration. Here we sought to characterise the innate immune clearance of apoptotic cells and its modulation by gingipains. We examined the capacity of gingipain-treated macrophages to migrate towards and phagocytose apoptotic cells. Lysine gingipain treatment of macrophages impaired macrophage migration towards apoptotic neutrophils. Furthermore, lysine gingipain treatment reduced surface expression levels of CD14, a key macrophage receptor for apoptotic cells, which resulted in reduced macrophage interactions with apoptotic cells. Additionally, while apoptotic cells and their derived secretome were shown to inhibit TNF-α-induced expression by P. gingivalis lipopolysaccharide, we demonstrated that gingipain preparations induced a rapid inflammatory response in macrophages that was resistant to the anti-inflammatory effects of apoptotic cells or their secretome. Taken together, these data indicate that P. gingivalis may promote the chronic inflammation seen in periodontal disease patients by multiple mechanisms, including rapid, potent gingipain-mediated inflammation, coupled with receptor cleavage leading to defective clearance of apoptotic cells and reduced anti-inflammatory responses. Thus, gingipains represent a potential therapeutic target for intervention in the management of chronic periodontal disease.
Highlights
Regulated tissue homeostasis is an essential physiological process, which is maintained through a fine balance of cell proliferation, cell differentiation and cell death
Evidence indicates that local tissue apoptosis drives the regulation of immune-inflammatory reactions, which occur in response to microbes producing anti-inflammatory signals affecting phagocytes at the site of infection.[10]
These assays revealed that both gingipain forms (Rgp and Kgp) were released into culture supernatant at significantly higher active amounts by strain HG66 compared with strain W83 (Figure 1a)
Summary
Regulated tissue homeostasis is an essential physiological process, which is maintained through a fine balance of cell proliferation, cell differentiation and cell death. The process of apoptosis that occurs during an inflammatory response supports the resolution of inflammation by the secretion of anti-inflammatory cytokines and pro-resolving molecules, which block further inflammatory cell infiltration and promotes recruitment of phagocytes which restore tissue homeostasis. Evidence indicates that local tissue apoptosis drives the regulation of immune-inflammatory reactions, which occur in response to microbes producing anti-inflammatory signals affecting phagocytes at the site of infection.[10] Defective control of the inflammatory response in this complex microenvironment can lead to the chronic, hyperinflammatory disease of periodontitis. Gingipains play a major role in the onset of inflammation by multiple mechanisms including: modifying the complement system; matrix metalloproteinase activity; neutrophil function; periodontal tissue vascular structure and responses; the host cytokine network and cell surface receptor levels.[15] Notably, gingipains have been shown to cleave key pattern recognition
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