The immunoproteasome is a specialized type of proteasome involved in MHC class I antigen presentation, antiviral adaptive immunity, autoimmunity, and is also part of a broader response to stress. Whether the immunoproteasome is regulated by DNA stress, however, is not known. We here demonstrate that mitochondrial DNA stress upregulates the immunoproteasome and MHC class I antigen presentation pathway via cGAS/STING/type I interferon signaling resulting in cell autonomous activation of CD8 ⁺ T cells. The cGAS/STING‐induced adaptive immune response is also observed in response to genomic DNA and is conserved in epithelial and mesenchymal cells of mice and men. In patients with idiopathic pulmonary fibrosis, chronic activation of the cGAS/STING‐induced adaptive immune response in aberrant lung epithelial cells concurs with CD8 ⁺ T‐cell activation in diseased lungs. Genetic depletion of the immunoproteasome and specific immunoproteasome inhibitors counteract DNA stress induced cytotoxic CD8 ⁺ T‐cell activation. Our data thus unravel cytoplasmic DNA sensing via the cGAS/STING pathway as an activator of the immunoproteasome and CD8 ⁺ T cells. This represents a novel potential pathomechanism for pulmonary fibrosis that opens new therapeutic perspectives.

Objective Adverse living standards are associated with poorer child health and safety. This study investigates whether adverse housing and neighbourhood conditions contribute to explain country-level associations between a country9s economic level and income inequality and child mortality, specifically injury mortality. Design Ecological, cross-sectional study. Setting/subjects Twenty-six European countries were grouped according to two country-level economic measures from Eurostat: gross domestic product (GDP) and income inequality. Adverse country-level housing and neighbourhood conditions were assessed using data from the 2006 European Union Income Social Inclusion and Living Conditions Database (n=203 000). Main outcome measure Child mortality incidence rates were derived for children aged 1–14 years for all causes, all injuries, road traffic injuries and unintentional injuries excluding road traffic. Linear regression analysis was applied to measure whether housing or neighbourhood conditions have a significant association with child mortality and whether a strain modified the association between GDP/income inequality and mortality. Results Country-level income inequality and GDP demonstrated a significant association with child mortality for all outcomes. A significant association was also found between housing strain and all child mortality outcomes, but not for neighbourhood strain. Housing strain partially modified the relationship between income inequality and GDP and all child mortality outcomes, with the exception of income inequality and road traffic injury mortality showing full mediation by housing strain. Conclusions Adverse housing conditions are a likely pathway in the country-level association between income inequality and economic GDP and child injury mortality.

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease characterized by excessive extracellular matrix deposition. Current IPF therapies slow disease progression but do not stop or reverse it. The (myo)fibroblasts are thought to be the main cellular contributors to excessive extracellular matrix production in IPF. Here we show that fibrotic alveolar type II cells regulate production and crosslinking of extracellular matrix via the co-transcriptional activator YAP. YAP leads to increased expression of Lysl oxidase (LOX) and subsequent LOX-mediated crosslinking by fibrotic alveolar type II cells. Pharmacological YAP inhibition via verteporfin reverses fibrotic alveolar type II cell reprogramming and LOX expression in experimental lung fibrosis in vivo and in human fibrotic tissue ex vivo. We thus identify YAP-TEAD/LOX inhibition in alveolar type II cells as a promising potential therapy for IPF patients.

Emphysema, the progressive destruction of gas exchange surfaces in the lungs, is a hallmark of COPD that is presently incurable. This therapeutic gap is largely due to a poor understanding of potential drivers of impaired tissue regeneration, such as abnormal lung epithelial progenitor cells, including alveolar type II (ATII) and airway club cells. We discovered an emphysema-specific subpopulation of ATII cells located in enlarged distal alveolar sacs, termed asATII cells. Single-cell RNA sequencing andin situlocalisation revealed that asATII cells co-express the alveolar marker surfactant protein C and the club cell marker secretaglobin-3A2 (SCGB3A2). A similar ATII subpopulation derived from club cells was also identified in mouse COPD models using lineage labelling. Human and mouse ATII subpopulations formed 80–90% fewer alveolar organoids than healthy controls, indicating reduced progenitor function. Targeting asATII cells or their progenitor club cells could reveal novel COPD treatment strategies.