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

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. Whi...

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Bibliographic Details
Published in:bioRxiv 2022-02
Main Authors: Ozanturk, Ayse N, Sahu, Sanjaya K, Kulkarni, Devesha H, Ma, Lina, Barve, Ruteja A, Mcphatter, Ja'nia, Garnica, Lorena, Dannull, Linus, Wu, Xiaobo, Brody, Steven L, Atkinson, John P, Kulkarni, Hrishikesh S
Format: Article
Language:English
Subjects:
Alternative pathway
Animal models
C3 gene
Cell death
Cell survival
Complement component C3
Epithelial cells
Lungs
Mucosa
Pneumonia
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Summary: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. Competing Interest Statement H.S.K. reports receiving grant funding for Alexion Pharmaceuticals unrelated to the submitted work. J.P.A. reports serving as a consultant for Celldex Therapeutics, Clinical Pharmacy Services, Kypha Inc., Achillion Pharmaceuticals Inc., and BioMarin Pharmaceutical Inc. and has stock or equity options in Compliment Corporation, Kypha Inc., Gemini Therapeutics, and Q32 Bio. S.L.B. has received laboratory research funds from Genentech. R.A.B. may receive royalty income based on the CompBIo method developed by R.A.B. and licensed by Washington University to PercayAI.
DOI:10.1101/2022.02.03.478963