Modulation of inflammasome activity by Porphyromonas gingivalis in periodontitis and associated systemic diseases

Abstract

Inflammasomes are large multiprotein complexes localized in the cytoplasm of the cell. They are responsible for the maturation of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as for the activation of inflammatory cell death, the so-called pyroptosis. Inflammasomes assemble in response to cellular infection, cellular stress, or tissue damage; promote inflammatory responses and are of great importance in regulating the innate immune system in chronic inflammatory diseases such as periodontitis and several chronic systemic diseases. In addition to sensing cellular integrity, inflammasomes are involved in the homeostatic mutualism between the indigenous microbiota and the host. There are several types of inflammasomes of which NLRP3 is best characterized in microbial pathogenesis. Many opportunistic bacteria try to evade the innate immune system in order to survive in the host cells. One of these is the periodontopathogen Porphyromonas gingivalis which has been shown to have several mechanisms of modulating innate immunity by limiting the activation of the NLRP3 inflammasome. Among them, ATP-/P2X7- signaling is recently associated not only with periodontitis but also with development of several systemic diseases. The present paper reviews multiple mechanisms through which P. gingivalis can modify innate immunity by affecting inflammasome activity.

Keywords: Porphyromonas gingivalis; inflammasomes; inflammation; innate immunity; periodontitis; persistence; subversion; systemic diseases.

Fig. 1

Major inflammasomes with known stimulators. In NLPR1 muramyl dipeptide and Bacillus anthracis lethal toxin can directly cause caspase-5 processing. NLRC4 activation is mostly related to components of Gram-negative bacteria. In AIM2, double-stranded DNA (dsDNA) binds to the HIN200 domain and requires ASC for processing of caspase-1. Also, NLPR3 requires ASC and caspase-1. It is activated in response to both exogenous and endogenous danger signals. (From ref. 19 with permission.)

Fig. 2

Activation of the NLRP3 inflammasome as a two-step mechanism. Primary signals come from activation of toll-like receptors (TLRs) which are responsible for the upregulation of NLRP3 and pro-interleukin-1β (IL-1β) in an NF-κB-dependent manner. Secondary signals come from several pathways: K⁺ efflux via P2X₇ receptor activation via ATPe coupling, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, NADPH oxidase, frustrated phagocytosis, and lysosomal rupture pathways. All these primary and secondary signals converge in the production of reactive oxygen species (ROS). (From ref. 19 with permission.)