Circulating complement proteins provide substantial protection against multiple infectious agents, although recent studies have shown that locally produced complement proteins can also serve tissue-specific roles. In Science Immunology, Sahu et al. show that complement produced locally in the lung epithelium lessens the tissue pathology that ensues after infection with Pseudomonas aeruginosa. Mice lacking liver-produced complement factor C3, the main source of systemic complement proteins, nevertheless were protected from severe bacterial pneumonia by airway epithelial cell (specifically club cell) production of C3. Curiously, the protective effect was not due to signaling via the anaphylatoxin C3a receptor; instead, local production of complement factor B (FB) was also required. Moreover, lung epithelial cells were protected against stress-induced cell death by intracellular C3 and FB, which were synthesized de novo by the airway epithelial cells within hours after infection. Club cell deficiency in either protein increased lung damage and inflammatory mediator production after acute bacterial infection. Lung epithelial cell death was associated with increased activation of poly(ADP-ribose) polymerase and caspases 3 and 8. How intracellular C3–Fb complexes prevent initiation of these cell-death executioners in stressed lung cells remains unclear at the moment, but these findings point to yet another way that complement proteins protect their host.
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