title: 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.
authors.affiliation: School of Life & Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham B4 7ET, UK.
authors.forename: Sowmya A
authors.initials: SA
authors.lastname: Castro
authors.affiliation: School of Life & Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham B4 7ET, UK.
authors.forename: Russell
authors.initials: R
authors.lastname: Collighan
authors.affiliation: School of Life & Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham B4 7ET, UK.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Lambert
authors.affiliation: School of Life & Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham B4 7ET, UK.
authors.forename: Irundika Hk
authors.initials: IH
authors.lastname: Dias
authors.affiliation: School of Life & Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham B4 7ET, UK.
authors.forename: Parbata
authors.initials: P
authors.lastname: Chauhan
authors.affiliation: School of Life & Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham B4 7ET, UK.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Bland
authors.affiliation: School of Life & Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham B4 7ET, UK.
authors.forename: Ivana
authors.initials: I
authors.lastname: Milic
authors.affiliation: School of Dentistry, University of Birmingham, Edgbaston, Birmingham B5 7EG, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Milward
authors.affiliation: School of Dentistry, University of Birmingham, Edgbaston, Birmingham B5 7EG, UK.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Cooper
authors.affiliation: School of Life & Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham B4 7ET, UK.
authors.forename: Andrew
authors.identifier: 0000-0002-4651-6761
authors.initials: A
authors.lastname: Devitt
mesh_terms: D018829:Adhesins, Bacterial / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D016866:Bacteroidaceae Infections / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D018441:Biofilms / Q000254:growth & development; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D057056:Cysteine Proteases / Q000378:metabolism; D000080867:Gingipain Cysteine Endopeptidases; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D009504:Neutrophils / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D010587:Phagocytosis / Q000502:physiology*; D016966:Porphyromonas gingivalis / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018829:Adhesins, Bacterial; D000080867:Gingipain Cysteine Endopeptidases; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D057056:Cysteine Proteases; D003546:Cysteine Endopeptidases