You have full access to this article via your institution.Download PDF The key neutrophil enzyme myeloperoxidase (MPO) is well known for its role in neutrophil extracellular traps. In a recent Nature work, Burn et al. now reveal for the first time MPO as a protein capable of modifying chromatin function into an immune effector, establishing a direct link between chromatin remodeling and innate immune defense.Neutrophils are the frontline guardians of immunity: rapidly migrating into inflamed tissue during injury, they are essential for pathogen clearance. Armed with a vast arsenal of antimicrobial mechanisms whose very potency comes at a cost — they can turn double-edged, inflicting collateral damage to host tissues — neutrophils keep these weapons under tight control, storing them in specialized granules until deployment is required.Alongside traditional defense tactics — phagocytosis accompanied by respiratory burst and degranulation leading to the release of proteolytic enzymes1 — recent attention has turned on a distinctive strategy: neutrophils produce web-like chromatin structures known as neutrophil extracellular traps (NETs),2 helping neutrophils trap and immobilize pathogens, thereby reinforcing host defense (Fig. 1a).1,3 Recent studies highlighted how DNA moonlights both as a structural and regulatory scaffold during NET formation, repurposed from its canonical role of genetic material into a dynamic scaffold that coordinates the assembly of these extracellular immune networks.4 In this framework, the structural and biochemical remodeling of chromatin directly governs the complex cascade of events that culminates in NETosis. Chromatin decondensation is indeed a critical and defining event: without this step NETs cannot form, making it both mechanistically and functionally crucial for innate immune defense.4Fig. 1: MPO-driven NETs supporting immune protection.a Traditional neutrophil defense tactics in immunity and NETs as a newly studied strategy where MPO has a key involvement. b Mechanistic model of the dual role of MPO in the context of NETs. After translocation to the nucleus (1), MPO monomers and dimers initially bind chromosomal DNA and the nucleosome acidic patch, triggering partial nucleosome unstacking and early chromatin decondensation (2). As dimeric MPO clashes one end of the nucleosomal DNA, as revealed by the refined three-dimensional structure, DNA is unwrapped leading to nucleosome disassembly and chromatin decondensation (3). In contrast, monomeric MPO avoids DNA clashes, remains bound to decondensed chromatin in mature NETs, and supports NET function through hypochlorous acid production (4). Figures adapted from1,5Full size imageInterestingly, NETs are decorated with an array of immune effector proteins, which serve distinct antimicrobial roles, pre-packaged within neutrophil granules and deployed only when required.2 This on-demand functionality raises intriguing questions: might these proteins, beyond their primary effector roles, also influence NET formation, and how do they engage with chromatin during its decondensation? A recent study by Burn et al.,5 published by Nature, has elucidated part of this complex biological process assigning a previously unrecognized regulatory role to the well-known myeloperoxidase (MPO). The authors proposed that MPO, long recognized for killing NET-trapped bacteria via the production of hypohalous acids, could be the prototype of a new class of proteins that transform chromatin into an immune effector. Notably, the study revealed an unanticipated dual role of MPO, not only leading to the formation of NETs, but also driving their downstream effector functions.How, then, does the association between MPO and chromatin contribute to NET biology? MPO displays a periodic pattern along NET filaments that exactly mirrors the spacing of nucleosomes. Using an array of high-resolution fluorescence microscopy techniques combined with complementary biochemical and immunological approaches, the authors demonstrated a tight correlation between MPO and nucleosome periodicity. MPO was consistently co-purified with histones and DNA from neutrophils in which NET formation was induced, forming stable MPO–nucleosome complexes only when nucleosomes remained intact. These specific interactions highlight the physiological importance of MPO in shaping both the structure and function of NETs, reinforcing the emerging evidence that MPO acts not only as a catalytic enzyme but also as a structural organizer of chromatin within extracellular traps.In their study, Burn et al. uncovered through cryo-electron tomography that NETs from healthy neutrophils contain nucleosome-sized particles within the dense DNA network, often observed together with electron densities corresponding to MPO, supporting the view of co-localization between MPO and nucleosomes. What makes the work by Burn et al. particularly significant is the original mechanistic model through which MPO fulfills two distinct previously un-proposed functions. Interestingly, they uncovered an oligomerization-dependent and non-catalytic function of MPO, dictating whether it promotes chromatin decondensation or stabilizes extracellular NETs, before engaging in its canonical bacteria-killing activity (Fig. 1b). The authors speculate that after nuclear translocation, MPO monomers and dimers bind chromatin, with dimers promoting DNA unwrapping and full nucleosome decondensation, while monomers remaining bound to decondensed chromatin supporting NET function through its traditional well-known catalytic activity in producing hypochlorous acid.Extending their findings to disease, the authors showed that NET-like structures in sputum from cystic fibrosis patients contained MPO–nucleosome complexes sensitive to DNase I digestion, indicating that MPO binding relies on intact DNA and reinforcing the nature of MPO–chromatin interactions within NETs. Several studies have shown that MPO-rich NETs contribute to disease progression in cancer and chronic inflammatory disorders — atherosclerosis and rheumatoid arthritis — where they enhance tumor metabolism and immune evasion or induce endothelial injury and cytokine release, ultimately sustaining inflammation and tissue damage.6,7,8 Building on these findings, with MPO emerging as a key stabilizer of NETs in vivo,5 the selective target of its non-canonical function could open new avenues to limit tissue damage and inflammation complementing recent strategies aimed at controlling the disease by modulating NET formation.8,9 In this regard, important question remain to be clarified: Which factors control the ratio between monomeric and dimeric MPOs? Is MPO enzymatic activity essential for NET formation? The authors partially tackled this latter issue by using a well-characterized MPO inhibitor. Remarkably, they found that the non-canonical role of MPO in chromatin binding and structural remodeling is independent of its catalytic activity, which remains fully functional in parallel. This intriguing separation of functions reveals a dual identity for MPO, combining both atypical structural and typical enzymatic roles in orchestrating NET formation and functionality, respectively.Overall, these findings depict MPO under a new light. Far from being merely an antimicrobial enzyme, MPO now emerges as both a catalytic and structural key component of innate immune architecture. With this study MPO establishes a previously unrecognized mechanism of chromatin reorganization: although it is not a classical chromatin remodeler, its activity defines a new class of chromatin-modifying factors that can adapt chromatin for immune defense.ReferencesKolaczkowska, E. & Kubes, P. Nat. Rev. Immunol. 13, 159–175 (2013).Article CAS PubMed Google Scholar Papayannopoulos, V. Nat. Rev. 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Biol. 11, 189–191 (2015).Article CAS PubMed PubMed Central Google Scholar Download referencesAcknowledgementsResearch in the lab on innate immunity and histone-modifying enzymes was supported by AIRC, the Italian Association for Cancer Research (IG19808; Fellowships 31561).Author informationAuthors and AffiliationsDepartment of Biology and Biotechnology, University of Pavia, Pavia, ItalySara Marchese & Andrea MatteviAuthorsSara MarcheseView author publicationsSearch author on:PubMed Google ScholarAndrea MatteviView author publicationsSearch author on:PubMed Google ScholarCorresponding authorsCorrespondence to Sara Marchese or Andrea Mattevi.Ethics declarationsCompeting interestsThe authors declare no competing interests.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Rights and permissionsReprints and permissionsAbout this article