Lung epithelial cell-derived C3 protects against pneumonia-induced lung injury

Abstract

The complement component C3 is a fundamental plasma protein for host defense. However, recent work has demonstrated the critical importance of local C3 expression in cell survival. Here we analyzed the effects of local versus peripheral sources of C3 expression in a model of bacterial pneumonia. While mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient in liver-deficient C3 remain protected, comparable to wildtype mice. Human lung transcriptome analysis showed secretory epithelial cells are a major source of C3. Mice with a C3 gene ablation from lung epithelial cells had worse pulmonary injury compared to wild type, despite maintaining normal circulating C3 levels. Finally, in human cellular and mouse pneumonia models, we show that C3 reduces epithelial cell death mediated through the alternative pathway component Factor B. Thus, our findings suggest that a locally-derived C3-Factor B pathway protects the lung mucosal barrier.

Intracellular complement: Evidence, definitions, controversies, and solutions

“…The traditionally understood roles of complement in innate immunity take place in the extracellular environment, directly opsonizing and even lysing some pathogens via the action of C3 deposition and formation of the terminal membrane attack complex 1 but also acting as a danger sensing mechanism, transmitting signals to cells via cell‐surface receptors of activated complement components 2 . While these functions have largely been attributed to circulating complement proteins secreted mainly from the liver, it has been recognized that local expression of complement proteins can also have an important role in tissues, 3 for example, in infection 4,5 and in complement‐dependent pathologies 6–8 . The discovery that some cell types express multiple complement proteins required for complete activation pathways, leading to spontaneous activation, also opened the possibility for autocrine complement activation playing roles in cellular homeostasis, activation, and inflammation 9,10 .…”