Biology subjects

Better, J.

Publications and source records attributed to Better, J..

3 recordsLinked to original sources

bioRxiv2026

Mitochondrial COX4I2 drives pericyte-dependent inflammation and emphysema

Chronic obstructive pulmonary disease (COPD) is characterized by neutrophilic inflammation, emphysema, and mild pulmonary hypertension (PH). Oxidative/nitrosative stress are key drivers, but specific mitochondrial mechanisms remain unclear. We show increased expression of the regulatory mitochondrial cytochrome c oxidase subunit 4 isoform 2 (COX4I2) in an early murine model and human COPD. After 8 months of cigarette smoke exposure, Cox4i2-/- mice were completely protected from emphysema but not from PH, associated with reduced nitrosative stress, inflammation, and apoptosis. Using a novel Cox4i2 reporter mouse and in situ hybridization of human lungs, COX4I2 was detected in precapillary ACTA2+ cells and capillary pericytes. COX4I2 promotes mitochondrial reactive oxygen species (mtROS) production in these cells, thereby enhancing neutrophil migration and alveolar type II cell apoptosis, and modulates angiogenesis. In contrast to Cox4i2-/-, mitochondria-targeted antioxidant MitoQ reversed emphysema and PH, suggesting pericyte-specific regulation of COPD pathologies and mtROS inhibition as a therapeutic approach in COPD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/703513v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@83bca4org.highwire.dtl.DTLVardef@d5ebaborg.highwire.dtl.DTLVardef@632d1borg.highwire.dtl.DTLVardef@1267a13_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

TNF Superfamily Member 14 Drives Post-Influenza Depletion of Alveolar Macrophages Enabling Secondary Pneumococcal Pneumonia

Secondary bacterial infection, often caused by Streptococcus pneumoniae (Spn), is one of the most frequent and severe complications of influenza A virus (IAV)-induced pneumonia. Phenotyping of the pulmonary innate immune landscape after IAV infection revealed a significant depletion of the tissue-resident alveolar macrophage (TR-AM) population at day 7, which was associated with increased susceptibility to Spn outgrowth. To elucidate the molecular mechanisms underlying TR-AM depletion, and to define putative targets for treatment, we combined single-cell transcriptomics and cell-specific PCR profiling in an unbiased manner, using in vivo models of IAV infection and IAV/Spn co-infection. The TNF superfamily 14 (TNFSF14) ligand-receptor axis was revealed as the driving force behind post-influenza TR-AM death during the early infection phase, enabling the transition to pneumococcal pneumonia, while intrapulmonary transfer of genetically modified TR-AMs and antibody-mediated neutralization of specific pathway components alleviated disease severity. With a mainly neutrophilic expression and a high abundance in the bronchoalveolar fluid (BALF) of patients with severe virus-induced ARDS, TNFSF14 emerged as a novel determinant of virus-driven lung injury. Targeting the TNFSF14-mediated intercellular communication network in the virus-infected lung can, therefore, improve host defense, minimizing the risk of subsequent bacterial pneumonia, and ameliorating disease outcome.

molecular biology↗

bioRxiv2023

Neutrophil efferocytosis reprograms mitochondrial metabolism to switch alveolar macrophages to a pro-resolution phenotype at the cost of bacterial control

Resolution of lung injuries is vital to maintain gas exchange. Concurrently, there is an increased risk of secondary bacterial infections. Alveolar macrophages (AMs) are crucial to clear bacteria and control initiation and resolution of inflammation, but environmental cues that switch functional phenotypes of AMs remain elusive. Here, we discovered an incapacity of AMs to mount an effective immune response to bacteria during resolution of inflammation. AM efferocytosis of neutrophils (PMNs), a hallmark of resolution of inflammation, switched mitochondrial metabolism to shift AM functions. Mechanistically, PMN-derived myeloperoxidase (MPO) fueled canonical glutaminolysis via uncoupling protein 2 (UCP2) resulting in decreased mtROS-dependent killing of bacteria and secretion of pro-inflammatory cytokines. Instead, MPO-enhanced UCP2 expression inhibited mitochondrial hyperpolarization and boosted efferocytosis irrespective of the presence of bacterial pathogens. In contrast, efferocytosis of epithelial cells resulted in a distinct anti-inflammatory phenotype of AMs maintaining phenotypic plasticity towards bacteria. Overall, uptake of apoptotic PMNs switches AMs to prioritize resolution of inflammation over antibacterial responses and similarly affects murine macrophages at extra-pulmonary sites, and human AMs. One sentence summaryNeutrophil efferocytosis reprograms mitochondrial metabolism to switch alveolar macrophages to a pro-resolution phenotype at the cost of bacterial control.

immunology↗