NLRP3 plays a major role in inflammasome activation during Mycoplasma pneumoniae infection

Abstract

Abstract Mycoplasma pneumoniae (Mp) is a common bacterial pathogen that causes acute and chronic airway diseases in humans and is a leading cause of bacterial community-acquired pneumonia and is implicated in initiation and exacerbation of asthma. Mp infection triggers a strong inflammatory response driven by interleukin-1β (IL-1β). Mp produces the Community-Acquired Respiratory Distress Syndrome (CARDS) toxin, which is highly expressed during infection and specifically activates the nod-like receptor family protein 3 (NLRP3) inflammasome. However, the significance of the NLRP3 inflammasome during Mp infection is unclear. The goal of our study is to characterize the inflammasome-mediated response during Mp infection. Wild-type (WT) and NLRP3 knockout (KO) bone-marrow derived macrophages (BMDMs) were infected with Mp and levels of proinflammatory cytokines and chemokines were measured by ELISA and immunoblot. Additionally, WT and NLRP3 KO C57 mice were inoculated intranasally with Mp and analyses were performed on cytokines and lung histopathology. Following Mp infection, NLRP3 KO BMDMs secreted significantly less IL-1β compared to WT BMDMs, yet IL-6 levels were similar. Analyses of bronchoalveolar lavage and lung tissue from Mp-infected WT and NLRP3 KO mice revealed a unique proinflammatory cytokine response, considerably enhanced disease and impaired bacterial clearance in NLRP3 KO mice. Our studies identified NLRP3 as a critical regulator of proinflammatory cytokine response and pathology during Mp infection. Future studies will focus on characterizing immune cell trafficking in the lungs during Mp infection and determining if Mp-related inflammasome activity is an ontogenic factor in initiating and exacerbating asthma.