Intracellular C3 Protects Human Airway Epithelial Cells from Stress-associated Cell Death

American Journal of Respiratory Cell and Molecular Biology
Hrishikesh S KulkarniJohn P Atkinson

Abstract

The complement system provides host defense against pathogens and environmental stress. C3, the central component of complement, is present in the blood and increases in BAL fluid after injury. We recently discovered that C3 is taken up by certain cell types and cleaved intracellularly to C3a and C3b. C3a is required for CD4+ T-cell survival. These observations made us question whether complement operates at environmental interfaces, particularly in the respiratory tract. We found that airway epithelial cells (AECs, represented by both primary human tracheobronchial cells and BEAS-2B [cell line]) cultured in C3-free media were unique from other cell types in that they contained large intracellular stores of de novo synthesized C3. A fraction of this protein reduced ("storage form") but the remainder did not, consistent with it being pro-C3 ("precursor form"). These two forms of intracellular C3 were absent in CRISPR knockout-induced C3-deficient AECs and decreased with the use of C3 siRNA, indicating endogenous generation. Proinflammatory cytokine exposure increased both stored and secreted forms of C3. Furthermore, AECs took up C3 from exogenous sources, which mitigated stress-associated cell death (e.g., from oxidative stress...Continue Reading

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Citations

May 11, 2019·Arthritis & Rheumatology·Alfred H J KimJohn P Atkinson
Apr 5, 2020·European Journal of Immunology·Ursula SmoleWinfried F Pickl
Aug 26, 2020·British Journal of Pharmacology·Jubayer RahmanClaudia Kemper
Jun 20, 2020·JCI Insight·Anuja JavaHrishikesh S Kulkarni
Jul 6, 2020·British Journal of Pharmacology·Ben C KingAnna M Blom
Apr 26, 2019·Frontiers in Immunology·Michelle ElvingtonJohn P Atkinson
May 7, 2020·American Journal of Respiratory and Critical Care Medicine·William BainJanet S Lee
Mar 31, 2021·Scandinavian Journal of Immunology·Juan Bautista De SanctisMarián Hajduch
Jun 24, 2021·Seminars in Immunopathology·B C King, A M Blom
Dec 17, 2021·Nature Reviews. Immunology·Behdad AfzaliClaudia Kemper

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Methods Mentioned

BETA
confocal microscopy
flow cytometry
flow-cytometry
environmental stress

Software Mentioned

GraphPad
Prism

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