Bacterial invasion via integrin alpha M induces activation of caspase-11 mediated noncanonical inflammasome.

Abstract

Periodontitis is a chronic inflammatory disease in oral tissue caused by subgingival bacterial biofilms, including Aggregatibacter actinomycetemcomitans （A. actinomycetemcomitans）, and is also well known as a risk factor or trigger of autoimmune diseases （e.g., rheumatoid arthritis, ulcerative colitis, multiple sclerosis）. Moreover, Aggressive or juvenile periodontitis also has a strong relation with A. actinomycetemcomitans. Periodontitis causes the production of inflammatory cytokines, such as Interleukin （IL）-1 or TNFα. The production is significant to form the pathology of periodontitis. However, the mechanism of the cytokine production is unclear. Among inflammatory cytokines, IL-1 is produced by the particular signaling pathway because this cytokine lacks the signal sequence for spontaneous secretion. The expressed pro-IL-1 is proteolytically processed by activated caspase-1 and converted as mature cytokines. The caspase-1 activation is regulated by inflammasome （a complex of caspase-1）. Recent studies showed that caspase-11 recognizes lipopolysaccharide （LPS） from Gram-negative bacteria resulting in noncanonical Nod like receptor pyrin domain containing 3 （NLRP3） inflammasome activation with IL-1β production and pyroptotic cell death．

In this study, we provided that A. actinomycetemcomitans enhances progression of arthritis in mice model including cell infiltration and IL-1β production in the paws, and induces noncanonical inflammasome activation in macrophages in a caspase-11-dependent manner. We also found that invasion of A. actinomycetemcomitans into macrophages via integrin alpha M （CD11b） is necessary to activate the noncanonical inflammasome. Furthermore, we exhibited anti-CD11b antibody and caspase-11 deficiency inhibits progression of arthritis with attenuation of IL-1β production in the paws in mice model. These data elucidate molecular mechanisms underlying A. actinomycetemcomitans trigger noncanonical inflammasome activation and exacerbating rheumatoid arthritis.