Role of the NK Cell-Activating Receptor CRACC in Periodontitis

Abstract

Periodontitis is a highly prevalent, biofilm-mediated chronic inflammatory disease that results in the loss of the tooth-supporting tissues. It features two major clinical entities: chronic periodontitis, which is more common, and aggressive periodontitis, which usually has an early onset and a rapid progression. Natural killer (NK) cells are a distinct subgroup of lymphocytes that play a major role in the ability of the innate immune system to steer immune responses. NK cells are abundant in periodontitis lesions, and NK cell activation has been causally linked to periodontal tissue destruction. However, the exact mechanisms of their activation and their role in the pathophysiology of periodontitis are elusive. Here, we show that the predominant NK cellactivating molecule in periodontitis is CD2-like receptor activating cytotoxic cells (CRACC). We show that CRACC induction was significantly more pronounced in aggressive than chronic periodontitis and correlated positively with periodontal disease severity, subgingival levels of specific periodontal pathogens, and NK cell activation in vivo. We delineate how Aggregatibacter actinomycetemcomitans, an oral pathogen that is causally associated with aggressive periodontitis, indirectly induces CRACC on NK cells via activation of dendritic cells and subsequent interleukin 12 (IL-12) signaling. In contrast, we demonstrate that fimbriae from Porphyromonas gingivalis, a principal pathogen in chronic periodontitis, actively attenuate CRACC induction on NK cells. Our data suggest an involvement of CRACC-mediated NK cell activation in periodontal tissue destruction and point to a plausible distinction in the pathobiology of aggressive and chronic periodontitis that may help explain the accelerated tissue destruction in aggressive periodontitis.

Natural Killer Cells in the Orchestration of Chronic Inflammatory Diseases

“…Increased type 1 cytokine production by both dendritic cells and NK cells, following exposition to P. gingivalis, has been described, resulting in increased P. gingivalis -specific IgG2 [81] (Figure 4(C)). Aggregatibacter actinomycetemcomitans, a gram-negative anaerobic bacterium strongly associated with localized aggressive periodontitis [82], has been reported to indirectly induces CD2-like receptor activating cytotoxic cells (CRACC) on NK cells, via activation of dendritic cells and subsequent IL-12 signalling [83]. CRACC induction was reported to be more significantly pronounced in aggressive than chronic periodontitis and positively correlated with periodontal disease severity, subgingival levels of specific periodontal pathogens, and NK cell activation in vivo [83] (Figure 4(D)).…”

The role of natural killer cells in periodontitis

“…In a recent study, Kramer et al. showed that the predominant natural killer cell activating molecule in periodontitis is CD2‐like receptor activating cytotoxic cells. The induction of CD2‐like receptor activating cytotoxic cells was significantly more pronounced in aggressive periodontitis than in chronic periodontitis and correlated positively with disease severity and natural killer cell activation.…”

Cytotoxic lymphocytes and atherosclerosis: significance, mechanisms and therapeutic challenges

“…In other studies, circulating but not lymph node CD56+ NK cells are reduced in patients with acute coronary syndrome compared with patients with stable angina (Backteman et al, ). Given that NK cells are activated in periodontitis (Kramer et al, ; Wang et al, ) and periodontitis has been associated with cardiovascular disease (Tonetti, Van Dyke, and Working group 1 of the joint EFPAAPw, ), it is surprising that the role of NK cells in periodontitis‐accelerated atherosclerosis has not been investigated. Similarly, whether NK cells contribute to CMV aggravated atherosclerosis has not been investigated (Vliegen et al, ; Beziat et al, ).…”