Inflammasome activation and CCR2-mediated monocyte-derived dendritic cell recruitment restrict Legionella pneumophila infection

Flagellin-induced NAIP/NLRC4 inflammasome activation and pyroptosis are critical events restricting Legionella pneumophila infection. However, the cellular and molecular dynamics of the in vivo responses against this bacterium are still unclear. We have found temporal coordination of two independent innate immunity pathways in controlling Legionella infection, the inflammasome activation and the CCR2-mediated Mo-DC recruitment. Inflammasome activation was an important player at the early stage of infection by lowering the numbers of bacteria for an efficient bacterial clearance conferred by the Mo-DC at the late stage of the infection. Mo-DC emergence highly depended on CCR2-signaling and dispensed inflammasome activation and pyroptosis. Also, Mo-DC compartment did not rely on the inflammasome machinery to deliver proper immune responses and was the most abundant cytokine-producing among the monocyte-derived cells in the infected lung. Importantly, when the CCR2- and NLRC4-dependent axes of response were simultaneously ablated, we observed an aggravated bacterial burden in the lung of infected mice. Taken together, we showed that inflammasome activation and CCR2-mediated immune response interplay in distinct pathways to restrict pulmonary bacterial infection. These findings extend our understanding of the in vivo integration and cooperation of different innate immunity arms in controlling infectious agents.

Automated summary

Flagellin-induced activation of NAIP/NLRC4 inflammasome and pyroptosis play critical roles in restricting Legionella pneumophila infection. In this study, we found temporal coordination of two independent innate immunity pathways, inflammasome activation and CCR2-mediated recruitment of Mo-DC, in controlling the infection. The inflammasome activation is important at the early stage of infection, while Mo-DC recruitment is crucial for efficient bacterial clearance at the late stage. Mo-DC emergence depends on CCR2-signaling and is independent of inflammasome activation and pyroptosis. Additionally, Mo-DC compartment produces the most cytokines among monocyte-derived cells in the infected lung. The simultaneous ablation of CCR2 and NLRC4 axes results in aggravated bacterial burden in the lung, indicating the interplay between inflammasome activation and CCR2-mediated immune response in restricting bacterial infection.