Infection of microglia with Porphyromonas gingivalis promotes cell migration and an inflammatory response through the gingipain-mediated activation of protease-activated receptor-2 in mice

Abstract

Despite a clear correlation between periodontitis and cognitive decline in Alzheimer’s disease, the precise mechanism underlying the relationship remains unclear. The periodontal pathogen Porphyromonas gingivalis produces a unique class of cysteine proteinases termed gingipains that comprises Arg-gingipain (Rgp) and Lys-gingipain (Kgp). Rgp and Kgp are important in the bacterial mediated host cell responses and the subsequent intracellular signaling in infected cells. In the present study, we attempted to clarify the potential effects of Rgp and Kgp on the cellular activation of brain-resident microglia. We provide the first evidence that Rgp and Kgp cooperatively contribute to the P. gingivalis-induced cell migration and expression of proinflammatory mediators through the activation of protease-activated receptor 2. The subsequent activation of phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase/ERK pathways contributes to cell migration and inflammatory response of microglia.

The Role of Periodontitis and Periodontal Bacteria in the Onset and Progression of Alzheimer’s Disease: A Systematic Review

“…These data are partly confirmed in a study by Hayashi et al in 2019 [10], who found a worsening of the ability to learn and memorize in middle age mice exposed to LPS-pg, and in a study by Liu et al in 2017 [13].…”

“…Liu instead sought to investigate the role of gingipain, which includes Arg-gingipain (Rgp) and Lys-gingipain (Kgp). These two molecules are a class of cysteine proteinases produced by Porphyromonas, providing the first evidence that these two proteases contribute cooperatively to the cell migration induced by P. gingivalis and the expression of proinflammatory mediators through the activation of the protease-activated receptor (PAR) 2 [13].…”

Keratinocyte-specific ablation of protease-activated receptor 2 prevents gingival inflammation and bone loss in a mouse model of periodontal disease

“…The process is initiated by infection with bacteria including Porphyromonas gingivalis , which relies on production of a group of cysteine proteases known as the gingipains for its pathogenicity (Bostanci & Belibasakis, ). Both the arginine‐specific gingipain B (RgpB) and the lysine‐specific gingipain (Kgp) activate the G‐protein‐coupled receptor, protease‐activated receptor 2 (PAR 2 ; Liu et al, , Lourbakos et al, ). This receptor is expressed by many cells present in the normal periodontal tissues, including oral epithelial cells, gingival fibroblasts, osteoblasts, and osteoclast precursors, as well as the neutrophils, macrophages, mast cells, and lymphocytes that are present once inflammation is established (Abraham et al, ; Bar‐Shavit et al, ; Belibasakis, Bostanci, & Reddi, ; D'Andrea, Rogahn, & Andrade‐Gordon, ; Lourbakos et al, ; Lourbakos et al, ; Smith et al, ).…”

Are Porphyromonas gingivalis Outer Membrane Vesicles Microbullets for Sporadic Alzheimer’s Disease Manifestation?

“…Liu et al [76] provided the first real evidence that infection of microglia with P. gingivalis promotes cell migration and an inflammatory response through the gingipain-mediated activation of protease-activated receptor-2 in mice. The subsequent activation of phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase/ERK pathways stimulated cell migration and an inflammatory response in microglia.…”