My research aims to uncover how redox metabolism regulates cellular functions. Reactive oxygen species (ROS) are molecules produced either through cellular metabolism or by immune cells to fight pathogens. Often compared to Dr. Jekyll and Mr. Hyde, ROS act as secondary messengers with essential signaling roles but can also cause oxidative damage if not properly regulated. Understanding how cells balance these dual roles is crucial for human health. My work focuses on how ROS metabolism influences redox signaling in immune cells, with three main areas of interest:
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1. ROS metabolism. Neutrophils are immune cells specialized in producing large amounts of reactive oxygen species (ROS) and hypohalous acids (HOX) to kill microbes. I recently demonstrated that superoxide dismutase 1 (SOD1) plays a crucial role in ROS formation and antimicrobial activity in neutrophils (Brinkmann, …, Foti. 2025. Journal of Immunology). Our findings revealed that SOD1 modulates the ratio of O2- to H2O2 during the ROS burst, thereby supporting myeloperoxidase (MPO) enzymatic activity. By employing biochemical, cell biological, and genetic approaches, we showed that SOD1 is crucial for ROS formation during NETosis and microbial microbial infections, as it reduces oxidative stress and enables complete neutrophil activation.
2. Redox signaling. ROS and HOX are reactive species tartgeting multiple biological molecules and modulating cellular functions such as neutrophil extracellular traps (NETs) formation. NETosis is the cellular pathway through which neutrophils deploy Neutrophil Extracellular Traps (NETs). The generation of reactive oxygen species (ROS) is a crucial step in this process. This is clearly evidenced by the failure of ROS-deficient patients to produce NETs. We demonstrate that ROS serve as a critical substrate for myeloperoxidase (MPO) to generate hypochlorous acid (HOCl), or "bleach," which acts as a fundamental mediator of NET formation (Foti. et al. manuscript in preparation). Specifically, HOCl chlorinates a class of lipids known as plasmalogens, yielding 2-chloro-palmitic acid (2-ClPA). We show that 2-ClPA, generated in situ during NETosis, is a key signaling molecule that triggers the liberation of Neutrophil Elastase (NE) from azurophilic granules. By altering granule membrane integrity, 2-ClPA induces the translocation of NE into the cytosol and subsequently the nucleus. Once nuclear, NE works in tandem with MPO to drive chromatin decondensation and nuclear expansion, ultimately resulting in the release of NETs.
Additionally, a major cellular target of ROS is the amino acid cysteine. By using a method named QTRP (quantitative thiol reactive profile) analysis, we are
able to detect the oxidized proteins and residues during the neutrophil activation. This approach led us to map the cysteine oxidative landscape in neutrophils (Foti et al, Manuscript in preparation).
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3. Antimicrobial synergism. We investigated how neutrophils enhance their microbicidal response through synergistic interactions between ROS and antimicrobial proteins. My recent work demonstrated a novel synergistic immunomodulatory mechanism: myeloperoxidase (MPO), an enzyme that converts H2O2 to bleach, chemically potentiates the antimicrobial peptide alpha defensin 1 (HNP1) (Foti et al, 2025. BioRxiv. In revision at Science). Patients with inflammatory lung diseases or infections generate significant levels of post-translationally halogenated HNP1-3 (Halo-HNP1-3), iodinated on Tyr 16 and chlorinated on Tyr 21. Interestingly, halogenation converts HNP1 into a potent chemokine and immunomodulator. These findings highlight a novel and key immunomodulatory mechanism during inflammation.
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