Purinergic signaling during Porphyromonas gingivalis infection

Abstract

Despite recent advances unraveling mechanisms of host-pathogen interactions in innate immunity, the participation of purinergic signaling in infection-driven inflammation remains an emerging research field with many unanswered questions. As one of the most-studied oral pathogens, Porphyromonas gingivalis is considered as a keystone pathogen with a central role in development of periodontal disease. This pathogen needs to evade immune-mediated defense mechanisms and tolerate inflammation in order to survive in the host. In this review, we summarize evidence showing that purinergic signaling modulates P. gingivalis survival and cellular immune responses, and discuss the role played by inflammasome activation and cell death during P. gingivalis infection.

Keywords: Inflammasome; Innate immunity; Oral microbes; P2X7 receptor; Porphyromonas gingivalis; Purinergic receptors.

Fig. 1

Schematic figure of the antagonistic effects of P1 and P2 receptors on infected cells. On the left, extracellular adenosine is recognized by P1 receptors (for example, A_2A and A_2B) and can promote pathogen survival or reversibly retard microbial growth. On the other hand, on the right, eATP released from stressed, dying or infected cells binds to P2 receptors (for example, P2X7) and leads to pathogen elimination through several pathways: (1) host cell death; (2) inflammasome activation and IL-1β secretion; (3) ROS and NO production; (4) or phospholipase D activation, promoting lysosome and phagosome fusion. Importantly, ecto-nucleotidases (E-NTPDases) from several pathogens inhibit pathogen elimination by eATP cleavage and/or favor microbial survival by generating extracellular adenosine.

Fig. 2

Schematic figure of the effects of P1 receptors, P2 receptors, and ecto-nucleotidases on P. gingivalis-induced inflammasome activation. (1) As the first signal required for inflammasome activation, P. gingivalis is recognized by the host cell through TLR2, and (2) reaches the cytosolic compartment. (3) Recognition of the bacterium via TLR2 promotes the translocation of the transcriptional factor NF-ĸB to the nucleus. (4) Once in the nucleus, NF-ĸB induces pro-inflammatory cytokines and transcription of inflammasome components (5) and promotes pro-IL-1β synthesis. (6) Concomitantly, P. gingivalis secretes NDK, which may be released to the extracellular compartment. (7) In addition, after infection, this oral bacterium induces ATP release from the host cell to the extracellular space. As a second signal for inflammasome activation, (8) ATP ligation to the P2X7 receptor can promote K⁺ efflux, ROS generation and/or lysosome damage, (9) which can activate the NLRP3 inflammasome. The NLRP3 inflammasome activates procaspase-1 to the mature caspase-1, and (10) this enzyme, in turn, proteolytically processes pro-IL-1β into IL-1β, (11) which is released from the cell. (12) NDK from P. gingivalis hydrolyzes eATP, generating its own metabolites, such as ADP, (13) which are recognized and cleaved via ecto-nucleotidases from the host, such as CD39, generating AMP. (14) AMP binds to CD73 on the host cell, and this enzyme can generate adenosine. (15) Adenosine interaction via adenosine receptor (16) can promote pro-IL-1β stability and thus, supports IL-1β secretion.