PTX3 Deficiency Aggravates Periodontitis by the Complement C5a-C5aR1 Axis.

Abstract

Dysregulation of the complement system plays a critical role in periodontitis progression. In addition to the harmful effects of biofilm, aberrant expression of complement regulatory proteins is also a potential cause of periodontitis. Pentraxin 3 (PTX3) is involved in complement activation and regulation, seeking a balance between amplifying complement-mediated immune responses and avoiding complement-mediated tissue damage. However, its role in periodontitis remains unexplored. This study aimed to investigate the effects of PTX3 on inflammation onset and resolution, with a particular emphasis on its complement regulatory function. We found that PTX3 is predominantly expressed in human and mouse inflammatory monocytes and is significantly upregulated during periodontitis. In vivo experiments showed that PTX3 deficiency led to the accumulation of complement C5a, massive infiltration of inflammatory monocytes, and alveolar bone loss in a ligation-induced mouse periodontitis model. Inhibition of C5a signaling with PMX53 or NLRP3 inflammasome with MCC950 significantly alleviated these adverse effects. In addition, PTX3 deficiency delayed the resolution of inflammation and alveolar bone repair during the recovery phase of periodontitis. In vitro studies showed that PTX3 deficiency promoted C5a conversion and release in monocytes, thereby activating the NLRP3 inflammasome via the C5a-C5aR1 axis-mediated mitogen-activated protein kinase and nuclear factor κB signaling in an inflammatory environment. In conclusion, these data elucidate the link between PTX3 in regulating complement activation and periodontitis progression, providing a potential target for innate immune-based therapy of periodontitis.