C3 is a central component of the complement system and one of the most abundant circulatory proteins. It is an early responder to injury and operates by killing pathogens and clearing debris. However, we have shown that it takes time for circulating C3 to reach the alveolar space in the setting of lung injury, thereby increasing the dependence on C3 present in the lung. We have also shown that not only is lung epithelial cell-derived C3 secreted, but also its intracellular stores are central to the protection against injury and cell death. These findings are a shift from the conventional thinking that liver-derived C3 is the main operational form of complement in the lung and increases the emphasis on epithelial cells as a source. Additionally, we have shown that many immune cell types—including alveolar macrophages—derive C3 stores via uptake from the extracellular space, and this uptake improves their effector response. Hence, an arm of our research program focuses on how complement proteins enhance immune responses at mucosal surfaces. These studies have implications not only for mitigating lung injury but also form the basis of testing the optimization of vaccine responses, and how the system affects chronic remodeling of the lung.

Representative publications

  1. Elvington M, Liszewski MK, Bertram P, Kulkarni HS, Atkinson JP. A C3(H20) recycling pathway is a component of the intracellular complement system. J Clin Invest. 2017 Mar 1;127(3):970-981. doi: 10.1172/JCI89412. Epub 2017 Feb 13. PMID: 28192370; PMCID: PMC5330788.
  2. Kulkarni HS, Elvington ML, Perng YC, Liszewski MK, Byers DE, Farkouh C, Yusen RD, Lenschow DJ, Brody SL, Atkinson JP. Intracellular C3 Protects Human Airway Epithelial Cells from Stress-associated Cell Death. Am J Respir Cell Mol Biol. 2019 Feb;60(2):144-157. doi: 10.1165/rcmb.2017-0405OC. PMID: 30156437; PMCID: PMC6376412.
  3. Earhart AP, Alburquerque RA, Starick M, Nallapu A, Garnica L, Ozanturk AN, Maurya RK, Wu X, Haspel JA, Kulkarni HS. The C3-C3aR axis modulates trained immunity in alveolar macrophages. bioRxiv [Preprint]. 2024 Nov 5:2024.11.01.621042. doi: 10.1101/2024.11.01.621042. PMID: 39554000; PMCID: PMC11565986.

Active and recently completed grants

  1. Lung epithelial cell-derived C3 in acute lung injury (National Institutes of Health)
  2. Harnessing the complement system to mitigate acute lung injury (Children’s Discovery Institute)