Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils

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.

Immunomodulatory effect of photodynamic therapy in Galleria mellonella infected with Porphyromonas gingivalis

“…P. gingivalis pathogenicity is related to the production of virulence factors including biofilm formation, several varieties of lipopolysaccharide and a family of proteases known as the gingipains, many of which play a role in the development and progression of periodontal disease [29,30]. In addition, in rodent models this bacteria has been associated with promoting a dysbiotic micro-flora and propagating a hyper-inflammatory process [31,32].…”

Oral Biofilms from Symbiotic to Pathogenic Interactions and Associated Disease –Connection of Periodontitis and Rheumatic Arthritis by Peptidylarginine Deiminase

“… Li et al (2013) demonstrated that P. gingivalis is able to reduce the expression of MIF mRNA in deep-pocket tissues ( Li et al, 2013 ). Furthermore, in vitro experiments demonstrated that treatment of macrophages with the lysine-specific gingipain Kgp impaired its migration to apoptotic neutrophils and reduced the anti-inflammatory effect of apoptotic cells, resulting a rapid inflammatory response, leading the authors to suggest that P. gingivalis promotes chronic inflammation by a gingipain-mediated defect in apoptotic cell clearance and resolution of tissue restoration ( Castro et al, 2017 ).…”

Integrating complement into the molecular pathogenesis of Hidradenitis Suppurativa

“…[40,41] Porphyromonas has also been implicated as an activator of both complement and the Th17 axis in chronic periodontitis, a mucosal disease featuring biofilm formation similar to HS. [44] Bacterial species can also directly activate C3aR1 and C5aR1 receptors via the action of PAMPs and DAMPs through direct cell contact. [44] Bacterial species can also directly activate C3aR1 and C5aR1 receptors via the action of PAMPs and DAMPs through direct cell contact.…”