Kinetics of local C3 production orchestrates neutrophil recruitment in lung injury.

Complement component 3 (C3) is crucial for host defense against bacteria. While the liver is the primary source of circulating C3, local C3 production at barrier surfaces such as the lung is key in early responses. Yet, how local complement-mediated responses are initiated at mucosal barriers-and how locally-derived C3 functions distinctly from its established cytoprotective role-is unknown. This study investigates the kinetics and necessity of lung-derived C3 during the initial hours of an infection. Leveraging models of bacterial pneumonia in ex vivo-perfused human lungs and mice deficient in liver-derived C3, we demonstrate that intrapulmonary C3 production and activation precedes the accumulation of circulating C3 into the bronchoalveolar space. Utilizing conditional knockout mice, we demonstrate that lung epithelial cell-derived C3 is required for early neutrophil recruitment in pneumonia. C3-mediated early neutrophil recruitment depends on a local C3a-C3aR axis that increases epithelial CXCL1 and CXCL2 production and occurs without any difference in epithelial injury, revealing that this activity is mechanistically different from its cytoprotective function. Collectively, our study demonstrates that an initial, entirely local phase of complement-mediated mucosal protection is critical for host defense during lung injury, before alveolar-capillary barrier disruption results in a subsequent, systemic response.