RESEARCH ARTICLE
Interplay between Porphyromonas gingivalis and EGF signalling
in the regulation of CXCL14
Jiamin Aw
†
|
Glen M. Scholz
†
|
Noorjahan Laila Huq
|
Jennifer Huynh
|
Neil M. O'Brien‐Simpson
|
Eric C. Reynolds
Oral Health Cooperative Research Centre,
Melbourne Dental School, Bio21 Molecular
Science and Biotechnology Institute,
University of Melbourne, Melbourne, Victoria,
Australia
Correspondence
Eric C. Reynolds, Oral Health Cooperative
Research Centre, Melbourne Dental School,
Bio21 Molecular Science and Biotechnology
Institute, University of Melbourne, Melbourne,
Victoria, Australia.
Email: e.reynolds@unimelb.edu.au
Present Address
Jennifer Huynh, Olivia Newton‐John Cancer
Research Institute and La Trobe University
School of Cancer Medicine, Victoria, Australia.
Funding information
Australian Government, Department of
Industry, Innovation and Science
Abstract
Porphyromonas gingivalis is a keystone pathogen in chronic periodontitis. Its expression
of gingipain proteases (Kgp and RgpA/B) is central to the stimulation of chronic inflam-
mation. In this study, we investigated the inflammatory response of oral epithelial cells
to P. gingivalis. The cells responded by upregulating the expression of the orphan che-
mokine CXCL14. The stimulation of CXCL14 expression was largely triggered by the
gingipain proteases and was dependent on the host protease‐activated receptor
PAR‐3. Significantly, CXCL14 expression was transcriptionally repressed in response
to epidermal growth factor (EGF)‐induced activation of the MEK‐ERK1/2 pathway.
P. gingivalis overcomes the repression of CXCL14 via the gingipain protease‐mediated
degradation of EGF. Therefore, P. gingivalis not only directly stimulates CXCL14
expression via PAR‐3 but also promotes its expression by antagonising EGF signalling.
In addition to chemotactic activity, some chemokines also have antimicrobial activities.
CXCL14 was demonstrated to have bactericidal activity, against commensal oral strep-
tococci associated with health. Notably though, P. gingivalis was not susceptible to kill-
ing by CXCL14, potentially because the gingipain proteases can degrade CXCL14. This
suggests that the stimulation of dysregulated CXCL14 expression by P. gingivalis may
help promote dysbiosis and the development of chronic periodontitis.
1
|
INTRODUCTION
The oral epithelium is a critical protective barrier to infection by micro-
bial pathogens. The barrier function of the epithelium is maintained
through cycles of cell proliferation and differentiation whereby basal
epithelial cells periodically withdraw from the cell cycle and terminally
differentiate as they migrate towards the epithelium surface (Presland
& Dale, 2000). Signalling by growth factor receptors, including the
epidermal growth factor (EGF) receptor, is important for maintaining
the homeostatic balance between epithelial cell proliferation and dif-
ferentiation (Parkar, Kuru, Giouzeli, & Olsen, 2001). Oral epithelial cells
also contribute to barrier function by producing antimicrobial peptides
(Dale & Fredericks, 2005). For example, the human β‐defensins, hBD1
and hBD2, which are expressed by differentiating epithelial cells in the
suprabasal layers of the gingival epithelium, are active against a range
of bacteria and fungi (Dale et al., 2001; Ouhara et al., 2005).
Oral epithelial cells also mediate host defence by triggering inflam-
mation in response to microbial pathogens. This is achieved through
the activation of pathogen recognition receptors (PRRs), including
Toll‐like receptors (TLRs) and protease‐activated receptors (PARs)
(Kinane, Galicia, Gorr, Stathopoulou, & Benakanakere, 2008; Uehara,
Imamura, Potempa, Travis, & Takada, 2008). Chemokines are impor-
tant mediators of the inflammatory responses activated by PRRs. Inter-
leukin‐8 (IL‐8) and chemokine (C‐X‐C motif) ligand 1 (CXCL1) stimulate
neutrophil recruitment, whereas chemokine (C‐C motif) ligand 2
(CCL2) stimulates the recruitment of monocytes and macrophages
ABBREVIATIONS: ActD, actinomycin D; CCL, chemokine (C‐C motif) ligand;
CXCL, chemokine (C‐X‐C motif) ligand; EGF, epidermal growth factor; hBD,
human β‐defensin; HPRT, hypoxanthine guanine phosphoribosyl transferase;
IL, interleukin; Kgp, Lysine‐specific gingipain; PAR, protease‐activated receptor;
PRR, pattern recognition receptor; Rgp, Arginine‐specific gingipain; TBP,
TATA‐box binding protein; TLCK, N‐α‐toysl‐L‐lysine chloromethyl ketone
hydrochloride; TLR, Toll‐like receptor
†
J. A. and G. M. S. contributed equally to this work.
Received: 14 September 2017 Accepted: 22 February 2018
DOI: 10.1111/cmi.12837
Cellular Microbiology. 2018;20:e12837.
https://doi.org/10.1111/cmi.12837
© 2018 John Wiley & Sons Ltdwileyonlinelibrary.com/journal/cmi 1of13
@Phil_Robichaud
@deepthiw
@JoseServera