Aggregatibacter actinomycetemcomitans, a potent immunoregulator of the periodontal host defense system and alveolar bone homeostasis

Abstract

Aggregatibacter actinomycetemcomitans is a perio-pathogenic bacteria that has long been associated with localized aggressive periodontitis. The mechanisms of its pathogenicity have been studied in humans and preclinical experimental models. Although different serotypes of A. actinomycetemcomitans have differential virulence factor expression, A. actinomycetemcomitans cytolethal distending toxin (CDT), leukotoxin, and lipopolysaccharide (LPS) have been most extensively studied in the context of modulating the host immune response. Following colonization and attachment in the oral cavity, A. actinomycetemcomitans employs CDT, leukotoxin, and LPS to evade host innate defense mechanisms and drive a pathophysiologic inflammatory response. This supra-physiologic immune response state perturbs normal periodontal tissue remodeling/turnover and ultimately has catabolic effects on periodontal tissue homeostasis. In this review, we have divided the host response into two systems: non-hematopoietic and hematopoietic. Non-hematopoietic barriers include epithelium and fibroblasts that initiate the innate immune host response. The hematopoietic system contains lymphoid and myeloid-derived cell lineages that are responsible for expanding the immune response and driving the pathophysiologic inflammatory state in the local periodontal microenvironment. Effector systems and signaling transduction pathways activated and utilized in response to A. actinomycetemcomitans will be discussed to further delineate immune cell mechanisms during A. actinomycetemcomitans infection. Finally, we will discuss the osteo-immunomodulatory effects induced by A. actinomycetemcomitans and dissect the catabolic disruption of balanced osteoclast-osteoblast-mediated bone remodeling, which subsequently leads to net alveolar bone loss.

Keywords: Aggregatibacter actinomycetemcomitans; inflammation; osteoblast; osteoclast; periodontitis.

Figure 1. Aggregatibacter actinomycetemcomitans colonizes the gingival sulcus by attachment to the sulcular/junctional epithelium cells

It subsequently invades through the epithelium via pro-apoptotic virulence mechanisms and penetrates into the subgingival connective tissue where is stimulates epithelial cells and fibroblasts to secrete pro-inflammatory cytokines (I). Neutrophils and monocytes are thereby recruited to the local site of infection and perpetuate the host inflammatory response Subsequently, B and T cells are recruited to the diseased periodontium from the circulation (II). T cells secrete pro-resorptive factors that drive osteoclast (OC) formation and drive bone resorption. Aggregatibacter actinomycetemcomitans simultaneously impairs osteoblast (OB) function, perturbing bone remodeling processes, which ultimately results in catabolic alveolar bone loss (III).

Figure 2. Aggregatibacter actinomycetemcomitans activates macrophage cell surface TLR2, TLR4, and LFA-1

TLR2 and TLR4 activation initiates JNK, ERK, p38 MAPKs and NF-kB intracellular signaling cascades that regulate pro-inflammatory cytokine transcription. MKP-1 negatively controls MAPK signaling by dephosphorylating p-JNK and p-p38. p38 activation leads to MK2 phosphorylation as an intermediate kinase in cytokine production. LFA-1, which is a heterodimer of CD18 and CD11a, initiates the inflammasome complex consisting of NLRs, ASC, and pro-caspase 1. Once activated, caspase-1 cleaves pro-IL-1β into mature IL-1β cytokine.

Figure 3. M-CSF release from osteoblasts lining alveolar bone stimulates defined osteoclast progenitors (dOCPs) to express the RANK receptor in preparation for a RANKL signaling response

Aggregatibacter actinomycetemcomitans stimulates RANKL, which is on the cell surface and secreted by osteoblasts, T-cells, and fibroblasts differentiates dOCPs into mononuclear pre-osteoclasts (pre-OCs) that are pushed toward the osteoclast (OC) lineage. Amid RANKL signaling, in the micro-environment pro-inflammatory cytokines TNF-α additively stimulates formation of TRAP positive multinucleated functional OCs. Aggregatibacter actinomycetemcomitans LPS also stimulates OC formation. Combined these A. actinomycetemcomitans –induced drivers of OC formation lead to mature OC formation and subsequent alveolar bone loss.