The Role of Complement Component C3 in Protection Against Pseudomonas Pneumonia-Induced Lung Injury

Abstract

The complement system is a family of proteins that facilitate immune resistance by attacking microbes to decrease pathogen burden. As a result, deficiencies of certain complement proteins result in recurrent bacterial infections, and can also result in acute lung injury (ALI). We and others have shown that C3 is present in both immune and nonimmune cells, and modulates cellular functions such as metabolism, differentiation, cytokine production, and survival. Although the emerging roles of the complement system have implications for host responses to ALI, key questions remain vis-a-vis the lung epithelium. In this review, we summarize our recent article in which we reported that during Pseudomonas aeruginosa-induced ALI, lung epithelial cell-derived C3 operates independent of liver-derived C3. Specifically, we report the use of a combination of human cell culture systems and global as well as conditional knockout mouse models to demonstrate the centrality of lung epithelial cell-derived C3. We also summarize recent articles that have interrogated the role of intracellular and/or locally derived C3 in host defense. We propose that C3 is a highly attractive candidate for enhancing tissue resilience in lung injury as it facilitates the survival and function of the lung epithelium, a key cell type that promotes barrier function.

Keywords: complement; lung injury; pneumonia.

FIG. 1.

The liver is the primary source of circulating C3 in the body. In comparison, lung-derived C3 is also present locally. (A) Upon infection with Pseudomonas aeruginosa, airway epithelial cells upregulate both C3 and Factor B, which increase Akt phosphorylation and mitigate the cleavage of PARP and caspase-3, thus facilitating cell survival. In the absence of C3 or Factor B, there is increased apoptosis in airway epithelial cells after infection. (B) Mice lacking C3 derived from the lungs (either global C3-deficient or epithelial cell-derived C3 deficient mice) have worse bacterial pneumonia at 24 h post-P. aeruginosa infection compared with those who are able to synthesize C3 from the lungs (wildtype mice, and those in whom C3 has only been deleted from the liver). The figure was created using biorender.com.