Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils: gingipains, apoptotic cell removal & inflammation

Sowmya A. Castro; Russell Collighan; Peter A. Lambert; Heraliyawala H.K. Dias; Parbata Chauhan; Charlotte E. Bland; Ivana Milic; Michael R. Millward; Paul R. Cooper; Andrew Devitt

doi:10.1038/cddis.2016.481

Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils: gingipains, apoptotic cell removal & inflammation

Sowmya A. Castro, Russell Collighan, Peter A. Lambert, Heraliyawala H.K. Dias, Parbata Chauhan, Charlotte E. Bland, Ivana Milic, Michael R. Millward, Paul R. Cooper, Andrew Devitt^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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, whilst apoptotic cells and their derived secretome were shown to inhibit TNF-α induced expression by P.gingivalis LPS, 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.

Original language	English
Article number	e2644
Number of pages	8
Journal	Cell Death and Disease
Volume	8
Issue number	3
DOIs	https://doi.org/10.1038/cddis.2016.481
Publication status	Published - 2 Mar 2017

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© The Author(s) 2017. Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the creditline; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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Porphyromonas gingivalis gingipains cause defective macrophage migration
© The Author(s) 2017. Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the creditline; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Accepted author manuscript, 1.04 MBLicence: CC BY 3.0

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Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils
Ajay Castro, S. (Creator), Collighan, R. (Creator), Lambert, P. (Creator), Dias, I. (Creator), Chauhan, P. (Creator), Clarke-Bland, C. (Creator), Milic, I. (Creator), Milward, M. (Creator), Cooper, P. R. (Creator) & Devitt, A. (Creator), Aston Data Explorer, 23 Feb 2017
DOI: 10.17036/researchdata.aston.ac.uk.00000202, https://www.nature.com/articles/cddis2016481
Dataset

Modelling Ageing Skeletal Muscle In Vitro to Determine the Effect of Aged Skeletal Muscle Secretomes on Macrophage Function and Their Role in Sarcopenia Progression
Chauhan, P. (Author), Devitt, A. (Supervisor) & Brown, J. (Supervisor), Jun 2022
Student thesis: Doctoral Thesis › Doctor of Philosophy

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Castro, S. A., Collighan, R., Lambert, P. A., Dias, H. H. K., Chauhan, P., Bland, C. E., Milic, I., Millward, M. R., Cooper, P. R., & Devitt, A. (2017). Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils: gingipains, apoptotic cell removal & inflammation. Cell Death and Disease, 8(3), Article e2644. https://doi.org/10.1038/cddis.2016.481

@article{f88c261d05ee416bb86455e9ff4bc0ad,

title = "Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils: gingipains, apoptotic cell removal & inflammation",

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, whilst apoptotic cells and their derived secretome were shown to inhibit TNF-α induced expression by P.gingivalis LPS, 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.",

author = "Castro, {Sowmya A.} and Russell Collighan and Lambert, {Peter A.} and Dias, {Heraliyawala H.K.} and Parbata Chauhan and Bland, {Charlotte E.} and Ivana Milic and Millward, {Michael R.} and Cooper, {Paul R.} and Andrew Devitt",

note = "{\textcopyright} The Author(s) 2017. Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in the creditline; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/",

year = "2017",

month = mar,

day = "2",

doi = "10.1038/cddis.2016.481",

language = "English",

volume = "8",

journal = "Cell Death and Disease",

issn = "2041-4889",

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number = "3",

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Castro, SA, Collighan, R , Lambert, PA, Dias, HHK, Chauhan, P, Bland, CE, Milic, I, Millward, MR, Cooper, PR & Devitt, A 2017, 'Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils: gingipains, apoptotic cell removal & inflammation', Cell Death and Disease, vol. 8, no. 3, e2644. https://doi.org/10.1038/cddis.2016.481

Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils: gingipains, apoptotic cell removal & inflammation. / Castro, Sowmya A.; Collighan, Russell ; Lambert, Peter A. et al.
In: Cell Death and Disease, Vol. 8, No. 3, e2644, 02.03.2017.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils

T2 - gingipains, apoptotic cell removal & inflammation

AU - Castro, Sowmya A.

AU - Collighan, Russell

AU - Lambert, Peter A.

AU - Dias, Heraliyawala H.K.

AU - Chauhan, Parbata

AU - Bland, Charlotte E.

AU - Milic, Ivana

AU - Millward, Michael R.

AU - Cooper, Paul R.

AU - Devitt, Andrew

N1 - © The Author(s) 2017. Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the creditline; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

PY - 2017/3/2

Y1 - 2017/3/2

N2 - 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, whilst apoptotic cells and their derived secretome were shown to inhibit TNF-α induced expression by P.gingivalis LPS, 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.

AB - 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, whilst apoptotic cells and their derived secretome were shown to inhibit TNF-α induced expression by P.gingivalis LPS, 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.

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UR - http://doi.org/10.17036/researchdata.aston.ac.uk.00000202

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U2 - 10.1038/cddis.2016.481

DO - 10.1038/cddis.2016.481

M3 - Article

AN - SCOPUS:85014440286

SN - 2041-4889

VL - 8

JO - Cell Death and Disease

JF - Cell Death and Disease

IS - 3

M1 - e2644

ER -

Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils: gingipains, apoptotic cell removal & inflammation

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

Student theses

Modelling Ageing Skeletal Muscle In Vitro to Determine the Effect of Aged Skeletal Muscle Secretomes on Macrophage Function and Their Role in Sarcopenia Progression

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