26 mars 2026
Pessoa et al. (BioRxiv) DOI: 10.1101/2025.09.22.677957
Keywords
COPD
IBD
Neutrophil
IFNα
Mitoferrin-1
IFNAR1
Mitochondria
Main Findings
Chronic obstructive pulmonary disease (COPD) is chronic, inflammatory lung disease in which neutrophil-driven inflammation drives progressive alveolar destruction. Likewise, in Inflammatory Bowel Disease (IBD) neutrophils drive autoinflammation leading to tissue damage. The mechanisms through which these inflammatory neutrophils are activated, and influence autoimmunity is not well understood. The preprint by Pessoa et al. aims to elucidate this inflammatory mechanism in neutrophils.
By reanalysing single-cell RNA-seq data from patients with these diseases, Pessoa et al. identified that neutrophils in these two conditions were enriched for IFN signalling as well as effector pathways including NETosis and degranulation. Using a CRISPR-Cas9 screen, SLC25A37, a regulator of mitochondrial iron transport, was identified as an essential component of for inflammatory neutrophil functions including NETosis, degranulation, cell migration, ROS production, and phagocytosis.
A novel mechanism was elucidated by which neutrophils sense NETosis products through TLR9, promoting increased mitoferrin-1 levels, mitochondrial fusion, and mitochondrial respiration. Extracellular TLRs, however, like TLR2 and TLR4, were found to promote mitochondrial fission and shift metabolism towards glycolysis, suggesting that neutrophils differentially alter their metabolism to respond to different pathogens.
Furthermore, it was found that the increase in Mitoferrin-1 and mitochondrial fusion, promoted by TLR9 antagonists, promotes the release of IFNα which is recognized by IFNAR1 though a positive feedback loop which, in turn, increases mitochondrial membrane potential and activates neutrophils. This feedback loop may be responsible for the chronic inflammation observed in diseases like COPD and IBD. It was further demonstrated that treatment with an IFNAR1-blocking antibody decreases chronic inflammation and neutrophil invasion in murine and organoid models of COPD and IBD.
Limitations & Suggestions
Major points
The evidence that mitochondrial dynamics are mediating this pathway is relatively weak with the current design. The addition of data demonstrating how stimulating mitochondrial fusion and/or fission impacts the proposed downstream pathway would demonstrate that the mitochondrial remodelling is truly essential for this pathway and not merely a side effect. If the title mentions mitochondrial remodelling, the effects of this remodelling should be investigated to determine it is a driving factor in this pathway.
In figure 4a, OCR of neutrophils with and without mitoferrin-1 is measured. The SLC25A37-knockout neutrophils appear to be consuming nearly no oxygen. What are the neutrophils doing metabolically if not mitochondrial OXPHOS? In addition, this raises concerns about the neutrophil viability. A SCENITH assay could be performed on the cells to determine the metabolic pathways being used, or if Mitoferrin-1 loss is decreasing viability.
Due to the conflicts with current literature on the impacts if IFNAR1 KO, a second mouse model for IBD, especially one that is more representative of chronic disease, would strengthen the argument that anti-IFNAR1 treatment reduced neutrophil-driven inflammation. Along this line of reasoning, a mouse model where IFNAR1 is conditionally knocked out of neutrophils would demonstrate that this proposed pathway and treatment are neutrophil specific.
Minor points
The separation of figures 3d-e from figure f and the different y-axes makes comparisons challenging. Furthermore, flow cytometry data should be represented consistently as either MFI or percentages for respective markers. While likely there are similar trends within the adult-derived in vitro differentiated neutrophils and fresh neutrophils, direct comparison is not possible. While this may be a preferential model to cord-derived neutrophils or HL-60 cells, these potential functional differences may still impact results.
It was not investigated whether cultured neutrophils differed metabolically from fresh cells, something that is very relevant in a paper suggesting metabolism is a mediator in the proposed pathway. Culturing cells in media may lead to changes in metabolism due to nutrient availability. Secondly, Luscombe et al. recently demonstrated that freezing cells may alter their metabolism.
The iron chelator Deferasirox (DFX) has several know off target effects including causing swelling of mitochondria (a side effect other iron chelators do not have). The addition of an alternative iron chelator would strengthen the assertion that iron is an essential mediator this pathway, and the inhibition of the proposed axis is not due to off target effects of DFX (Gottwald et al., 2020).
Significance/Novelty
This preprint by Pessoa et al. discovers a novel pathway by which neutrophils-driven chronic inflammation contributes to both IBD and COPD. This work adds to a growing body of research that investigating the interplay between metabolism and immune dysfunction.
Credit
Reviewed by Meredith Crockett as part of a cross-institutional journal club between the Max-Delbrück Center Berlin, the Ragon Institute Boston (Mass General, MIT, Harvard), the University of Virginia, the Medical University of Vienna and other life science institutes in Vienna.
The author declares no conflict of interests in relation to their involvement in the review.
Sources:
“Chronic Obstructive Pulmonary Disease (COPD).” World Health Organization, World Health Organization, www.who.int/news-room/fact-sheets/detail/chronic-obstructive- pulmonary-disease (copd)#:~:text=Key%20facts,risk%20of%20other%20health%20problems. Accessed 11 Nov. 2025.
Gottwald, Esther M., et al. “The iron chelator Deferasirox causes severe mitochondrial swelling without depolarization due to a specific effect on inner membrane permeability.” Scientific Reports, vol. 10, no. 1, 31 Jan. 2020, https://doi.org/10.1038/s41598-020-58386-9
Lewis, James D., et al. “Incidence, prevalence, and racial and ethnic distribution ofinflammatory bowel disease in the United States.” Gastroenterology, vol. 165, no. 5, Nov. 2023, https://doi.org/10.1053/j.gastro.2023.07.003
Luscombe, Curtis, et al. “Impact of cryopreservation on immune cell metabolism as measured by SCENITH.”Oxford Open Immunology, vol. 6, no. 1, 20 Dec. 2024, https://doi.org/10.1093/oxfimm/iqae015.