Abstract
Porphyromonas gingivalis is a gram-negative anaerobic periodontal pathogen that persists in dysbiotic mixed-species biofilms alongside a dense inflammatory infiltrate of neutrophils and other leukocytes in the subgingival areas of the periodontium. Toll-like receptor 2 (TLR2) mediates the inflammatory response to P. gingivalis and TLR2-deficient mice resist alveolar bone resorption following oral challenge with this organism. Although, MyD88 is an adaptor protein considered necessary for TLR2-induced inflammation, we now report for the first time that oral challenge with P. gingivalis leads to alveolar bone resorption in the absence of MyD88. Indeed, in contrast to prototypical TLR2 agonists, such as the lipopeptide Pam3CSK4 that activates TLR2 in a strictly MyD88-dependent manner, P. gingivalis strikingly induced TLR2 signaling in neutrophils and macrophages regardless of the presence or absence of MyD88. Moreover, genetic or antibody-mediated inactivation of TLR2 completely reduced cytokine production in P. gingivalis-stimulated neutrophils or macrophages, suggesting that TLR2 plays a non-redundant role in the host response to P. gingivalis. In the absence of MyD88, inflammatory TLR2 signaling in P. gingivalis-stimulated neutrophils or macrophages depended upon PI3K. Intriguingly, TLR2-PI3K signaling was also critical to P. gingivalis evasion of killing by macrophages, since their ability to phagocytose this pathogen was reduced in a TLR2 and PI3K-dependent manner. Moreover, within those cells that did phagocytose bacteria, TLR2-PI3K signaling blocked phago-lysosomal maturation, thereby revealing a novel mechanism whereby P. gingivalis can enhance its intracellular survival. Therefore, P. gingivalis uncouples inflammation from bactericidal activity by substituting TLR2-PI3K in place of TLR2-MyD88 signaling. These findings further support the role of P. gingivalis as a keystone pathogen, which manipulates the host inflammatory response in a way that promotes bone loss but not bacterial clearance. Modulation of these host response factors may lead to novel therapeutic approaches to improve outcomes in disease conditions associated with P. gingivalis.
Highlights
Bone resorption is a prominent feature of chronic conditions of microbial etiology, such as osteomyelitis and periodontitis
Repeated oral inoculation of mice with P. gingivalis leads to its colonization, quantitative and compositional alterations to the periodontal microbiota and the induction of an acute inflammatory infiltrate in the gingival tissue dominated by neutrophils and monocyte/macrophages, which in turn contribute to bone resorption surrounding the teeth (Baker et al, 2000; Burns et al, 2006; Hajishengallis et al, 2011; Papadopoulos et al, 2013)
Our study shows for the first time that P. gingivalisinduced bone loss is Toll-Like Receptor 2 (TLR2)-dependent but MyD88-independent
Summary
Bone resorption is a prominent feature of chronic conditions of microbial etiology, such as osteomyelitis and periodontitis. TLR2-driven inflammation is normally linked to bactericidal activity and to osteoclast activation and bone loss through signaling initiated by the intracellular adaptor protein MyD88 (Pandey et al, 2014). MyD88 has been linked to a number of pathological inflammatory conditions (Kfoury et al, 2014; Kassem et al, 2015a), we demonstrate here that P. gingivalis induces bone resorption independently of MyD88. The MyD88-independent TLR2 activation induced by P. gingivalis stimulates PI3K signaling that drives inflammation but at the same time depresses phagocytosis and enables phagocytosed bacteria to escape lysosomal degradation. Activation of TLR2-PI3K occurs independently of MyD88 and is critical for P. gingivalis to escape immunity and drive inflammatory bone resorption. Understanding the mechanisms that uncouple inflammation from bactericidal activity can lead to novel therapeutic approaches for chronic inflammatory tissue damage associated with dysbiotic microbiota
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