Aryl hydrocarbon receptor activation alters immune cell populations in the lung and bone marrow during coronavirus infection.

Respiratory viral infections are one of the major causes of illness and death worldwide. Symptoms associated with respiratory infections can range from mild to severe, and there is limited understanding of why there is large variation in severity. Environmental exposures are a potential causative factor. The aryl hydrocarbon receptor (AHR) is an environment-sensing molecule expressed in all immune cells. Although there is considerable evidence that AHR signaling influences immune responses to other immune challenges, including respiratory pathogens, less is known about the impact of AHR signaling on immune responses during coronavirus (CoV) infection. In this study, we report that AHR activation significantly altered immune cells in the lungs and bone marrow of mice infected with a mouse CoV. AHR activation transiently reduced the frequency of multiple cells in the mononuclear phagocyte system, including monocytes, interstitial macrophages, and dendritic cells in the lung. In the bone marrow, AHR activation altered myelopoiesis, as evidenced by a reduction in granulocyte-monocyte progenitor cells and an increased frequency of myeloid-biased progenitor cells. Moreover, AHR activation significantly affected multiple stages of the megakaryocyte lineage. Overall, these findings indicate that AHR activation modulates multiple aspects of the immune response to a CoV infection. Given the significant burden of respiratory viruses on human health, understanding how environmental exposures shape immune responses to infection advances our knowledge of factors that contribute to variability in disease severity and provides insight into novel approaches to prevent or treat disease.NEW & NOTEWORTHY Our study reveals a multifaceted role for aryl hydrocarbon receptor (AHR) signaling in the immune response to coronavirus (CoV) infection. Sustained AHR activation during in vivo mouse CoV infection altered the frequency of mature immune cells in the lung and modulated emergency hematopoiesis, specifically myelopoiesis and megakaryopoiesis, in bone marrow. This provides new insight into immunoregulation by the AHR and extends our understanding of how environmental exposures can impact host responses to respiratory viral infections.

Timing influences the impact of aryl hydrocarbon receptor activation on the humoral immune response to respiratory viral infection.

Humoral responses to respiratory viruses, such as influenza viruses, develop over time and are central to protection from repeated infection with the same or similar viruses. Epidemiological and experimental studies have linked exposures to environmental contaminants that bind the aryl hydrocarbon receptor (AHR) with modulated antibody responses to pathogenic microorganisms and common vaccinations. Other studies have prompted investigation into the potential therapeutic applications of compounds that activate AHR. Herein, using two different AHR ligands [2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester (ITE), to modulate the duration of AHR activity, we show that the humoral response to viral infection is dependent upon the duration and timing of AHR signaling, and that different cellular elements of the response have different sensitivities. When AHR activation was initiated prior to infection with influenza A virus, there was suppression of all measured elements of the humoral response (i.e., the frequency of T follicular helper cells, germinal center B cells, plasma cells, and circulating virus-specific antibody). However, when the timing of AHR activation was adjusted to either early (days -1 to +5 relative to infection) or later (days +5 onwards), then AHR activation affected different aspects of the overall humoral response. These findings highlight the importance of considering the timing of AHR activation in relation to triggering an immune response, particularly when targeting the AHR to manipulate disease processes.

Dry-Cleaning Chemicals and a Cluster of Parkinson's Disease and Cancer: A Retrospective Investigation.

BACKGROUND: Environmental exposure to trichloroethylene (TCE), a carcinogenic dry-cleaning chemical, may be linked to Parkinson's disease (PD). OBJECTIVE: The objective of this study was to determine whether PD and cancer were elevated among attorneys who worked near a contaminated site. METHODS: We surveyed and evaluated attorneys with possible exposure and assessed a comparison group. RESULTS: Seventy-nine of 82 attorneys (96.3%; mean [SD] age: 69.5 [11.4] years; 89.9% men) completed at least one phase of the study. For comparison, 75 lawyers (64.9 [10.2] years; 65.3% men) underwent clinical evaluations. Four (5.1%) of them who worked near the polluted site reported PD, more than expected based on age and sex (1.7%; P = 0.01) but not significantly higher than the comparison group (n = 1 [1.3%]; P = 0.37). Fifteen (19.0%), compared to four in the comparison group (5.3%; P = 0.049), had a TCE-related cancer. CONCLUSIONS: In a retrospective study, diagnoses of PD and TCE-related cancers appeared to be elevated among attorneys who worked next to a contaminated dry-cleaning site. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Aryl Hydrocarbon Receptor Modulates T Follicular Helper Cell Responses to Influenza Virus Infection in Mice.

T follicular helper (Tfh) cells support Ab responses and are a critical component of adaptive immune responses to respiratory viral infections. Tfh cells are regulated by a network of signaling pathways that are controlled, in part, by transcription factors. The aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that modulates many aspects of adaptive immunity by binding a range of small molecules. However, the contribution of AHR signaling to Tfh cell differentiation and function is not known. In this article, we report that AHR activation by three different agonists reduced the frequency of Tfh cells during primary infection of C57BL/6 mice with influenza A virus (IAV). Further, using the high-affinity and AHR-specific agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin, we show that AHR activation reduced Tfh cell differentiation and T cell-dependent B cell responses. Using conditional AHR knockout mice, we demonstrated that alterations of Tfh cells and T cell-dependent B cell responses after AHR activation required the AHR in T cells. AHR activation reduced the number of T follicular regulatory (Tfr) cells; however, the ratio of Tfr to Tfh cells was amplified. These alterations to Tfh and Tfr cells during IAV infection corresponded with differences in expression of BCL6 and FOXP3 in CD4+ T cells and required the AHR to have a functional DNA-binding domain. Overall, these findings support that the AHR modulates Tfh cells during viral infection, which has broad-reaching consequences for understanding how environmental factors contribute to variation in immune defenses against infectious pathogens, such as influenza and severe acute respiratory syndrome coronavirus.

Diacetyl inhalation impairs airway epithelial repair in mice infected with influenza A virus.

Bronchiolitis obliterans (BO) is a debilitating disease of the small airways that can develop following exposure to toxic chemicals as well as respiratory tract infections. BO development is strongly associated with diacetyl (DA) inhalation exposures at occupationally relevant concentrations or severe influenza A viral (IAV) infections. However, it remains unclear whether lower dose exposures or more mild IAV infections can result in similar pathology. In the current work, we combined these two common environmental exposures, DA and IAV, to test whether shorter DA exposures followed by sublethal IAV infection would result in similar airways disease. Adult mice exposed to DA vapors 1 h/day for 5 consecutive days followed by infection with the airway-tropic IAV H3N2 (HKx31) resulted in increased mortality, increased bronchoalveolar lavage (BAL) neutrophil percentage, mixed obstruction and restriction by lung function, and subsequent airway remodeling. Exposure to DA or IAV alone failed to result in significant pathology, whereas mice exposed to DA + IAV showed increased α-smooth muscle actin (αSMA) and epithelial cells coexpressing the basal cell marker keratin 5 (KRT5) with the club cell marker SCGB1A1. To test whether DA exposure impairs epithelial repair after IAV infection, mice were infected first with IAV and then exposed to DA during airway epithelial repair. Mice exposed to IAV + DA developed similar airway remodeling with increased subepithelial αSMA and epithelial cells coexpressing KRT5 and SCGB1A1. Our findings reveal an underappreciated concept that common environmental insults while seemingly harmless by themselves can have catastrophic implications on lung function and long-term respiratory health when combined.

Dung biomass smoke exposure impairs resolution of inflammatory responses to influenza infection.

Epidemiological studies associate biomass smoke with an increased risk for respiratory infections in children and adults in the developing world, with 500,000 premature deaths each year attributed to biomass smoke-related acute respiratory infections including infections caused by respiratory viruses. Animal dung is a biomass fuel of particular concern because it generates more toxic compounds per amount burned than wood, and is a fuel of last resort for the poorest households. Currently, there is little biological evidence on the effects of dung biomass smoke exposure on immune responses to respiratory viral infections. Here, we investigated the impact of dung biomass exposure on respiratory infection using a mouse model of dung biomass smoke and cultured primary human small airway epithelial cells (SAECs). Mice infected with influenza A virus (IAV) after dung biomass smoke exposure had increased mortality, lung inflammation and virus mRNA levels, and suppressed expression of innate anti-viral mediators compared to air exposed mice. Importantly, there was still significant tissue inflammation 14 days after infection in dung biomass smoke-exposed mice even after inflammation had resolved in air-exposed mice. Dung biomass smoke exposure also suppressed the production of anti-viral cytokines and interferons in cultured SAECs treated with poly(I:C) or IAV. This study shows that dung biomass smoke exposure impairs the immune response to respiratory viruses and contributes to biomass smoke-related susceptibility to respiratory viral infections, likely due to a failure to resolve the inflammatory effects of biomass smoke exposure.

Old Receptor, New Tricks-The Ever-Expanding Universe of Aryl Hydrocarbon Receptor Functions. Report from the 4th AHR Meeting, 29⁻31 August 2018 in Paris, France.

In a time where "translational" science has become a mantra in the biomedical field, it is reassuring when years of research into a biological phenomenon suddenly points towards novel prevention or therapeutic approaches to disease, thereby demonstrating once again that basic science and translational science are intimately linked. The studies on the aryl hydrocarbon receptor (AHR) discussed here provide a perfect example of how years of basic toxicological research on a molecule, whose normal physiological function remained a mystery for so long, has now yielded a treasure trove of actionable information on the development of targeted therapeutics. Examples are autoimmunity, metabolic imbalance, inflammatory skin and gastro-intestinal diseases, cancer, development and perhaps ageing. Indeed, the AHR field no longer asks, "What does this receptor do in the absence of xenobiotics?" It now asks, "What doesn't this receptor do?".

Alternative Progenitor Lineages Regenerate the Adult Lung Depleted of Alveolar Epithelial Type 2 Cells.

An aberrant oxygen environment at birth increases the severity of respiratory viral infections later in life through poorly understood mechanisms. Here, we show that alveolar epithelial cell (AEC) 2 cells (AEC2s), progenitors for AEC1 cells, are depleted in adult mice exposed to neonatal hypoxia or hyperoxia. Airway cells expressing surfactant protein (SP)-C and ATP binding cassette subfamily A member 3, alveolar pod cells expressing keratin (KRT) 5, and pulmonary fibrosis were observed when these mice were infected with a sublethal dose of HKx31, H3N2 influenza A virus. This was not seen in infected siblings birthed into room air. Genetic lineage tracing studies in mice exposed to neonatal hypoxia or hyperoxia revealed pre-existing secretoglobin 1a1+ cells produced airway cells expressing SP-C and ATP binding cassette subfamily A member 3. Pre-existing Kr5+ progenitor cells produced squamous alveolar cells expressing receptor for advanced glycation endproducts, aquaporin 5, and T1α in alveoli devoid of AEC2s. They were not the source of KRT5+ alveolar pod cells. These oxygen-dependent changes in epithelial cell regeneration and fibrosis could be recapitulated by conditionally depleting AEC2s in mice using diphtheria A toxin and then infecting with influenza A virus. Likewise, airway cells expressing SP-C and alveolar cells expressing KRT5 were observed in human idiopathic pulmonary fibrosis. These findings suggest that alternative progenitor lineages are mobilized to regenerate the alveolar epithelium when AEC2s are severely injured or depleted by previous insults, such as an adverse oxygen environment at birth. Because these lineages regenerate AECs in spatially distinct compartments of a lung undergoing fibrosis, they may not be sufficient to prevent disease.

The Oxygen Environment at Birth Specifies the Population of Alveolar Epithelial Stem Cells in the Adult Lung.

Alveolar epithelial type II cells (AEC2) maintain pulmonary homeostasis by producing surfactant, expressing innate immune molecules, and functioning as adult progenitor cells for themselves and alveolar epithelial type I cells (AEC1). How the proper number of alveolar epithelial cells is determined in the adult lung is not well understood. Here, BrdU labeling, genetic lineage tracing, and targeted expression of the anti-oxidant extracellular superoxide dismutase in AEC2s are used to show how the oxygen environment at birth influences postnatal expansion of AEC2s and AEC1s in mice. Birth into low (12%) or high (≥60%) oxygen stimulated expansion of AEC2s through self-renewal and differentiation of the airway Scgb1a1 + lineage. This non-linear or hormesis response to oxygen was specific for the alveolar epithelium because low oxygen stimulated and high oxygen inhibited angiogenesis as defined by changes in V-cadherin and PECAM (CD31). Although genetic lineage tracing studies confirmed adult AEC2s are stem cells for AEC1s, we found no evidence that postnatal growth of AEC1s were derived from self-renewing Sftpc + or the Scbg1a1 + lineage of AEC2s. Taken together, our results show how a non-linear response to oxygen at birth promotes expansion of AEC2s through two distinct lineages. Since neither lineage contributes to the postnatal expansion of AEC1s, the ability of AEC2s to function as stem cells for AEC1s appears to be restricted to the adult lung. Stem Cells 2016;34:1396-1406.

Linking the aryl hydrocarbon receptor with altered DNA methylation patterns and developmentally induced aberrant antiviral CD8+ T cell responses.

Successfully fighting infection requires a properly tuned immune system. Recent epidemiological studies link exposure to pollutants that bind the aryl hydrocarbon receptor (AHR) during development with poorer immune responses later in life. Yet, how developmental triggering of AHR durably alters immune cell function remains unknown. Using a mouse model, we show that developmental activation of AHR leads to long-lasting reduction in the response of CD8(+) T cells during influenza virus infection, cells critical for resolving primary infection. Combining genome-wide approaches, we demonstrate that developmental activation alters DNA methylation and gene expression patterns in isolated CD8(+) T cells prior to and during infection. Altered transcriptional profiles in CD8(+) T cells from developmentally exposed mice reflect changes in pathways involved in proliferation and immunoregulation, with an overall pattern that bears hallmarks of T cell exhaustion. Developmental exposure also changed DNA methylation across the genome, but differences were most pronounced following infection, where we observed inverse correlation between promoter methylation and gene expression. This points to altered regulation of DNA methylation as one mechanism by which AHR causes durable changes in T cell function. Discovering that distinct gene sets and pathways were differentially changed in developmentally exposed mice prior to and after infection further reveals that the process of CD8(+) T cell activation is rendered fundamentally different by early life AHR signaling. These findings reveal a novel role for AHR in the developing immune system: regulating DNA methylation and gene expression as T cells respond to infection later in life.

Demographic, Reproductive, and Dietary Determinants of Perfluorooctane Sulfonic (PFOS) and Perfluorooctanoic Acid (PFOA) Concentrations in Human Colostrum.

To determine demographic, reproductive, and maternal dietary factors that predict perfluoroalkyl substance (PFAS) concentrations in breast milk, we measured perfluorooctane sulfonic (PFOS) and perfluorooctanoic acid (PFOA) concentrations, using liquid chromatography-mass spectrometry, in 184 colostrum samples collected from women participating in a cohort study in Eastern Slovakia between 2002 and 2004. During their hospital delivery stay, mothers completed a food frequency questionnaire, and demographic and reproductive data were also collected. PFOS and PFOA predictors were identified by optimizing multiple linear regression models using Akaike's information criterion (AIC). The geometric mean concentration in colostrum was 35.3 pg/mL for PFOS and 32.8 pg/mL for PFOA. In multivariable models, parous women had 40% lower PFOS (95% CI: -56 to -17%) and 40% lower PFOA (95% CI: -54 to -23%) concentrations compared with nulliparous women. Moreover, fresh/frozen fish consumption, longer birth intervals, and Slovak ethnicity were associated with higher PFOS and PFOA concentrations in colostrum. These results will help guide the design of future epidemiologic studies examining milk PFAS concentrations in relation to health end points in children.

Neonatal hyperoxia leads to persistent alterations in NK responses to influenza A virus infection.

Respiratory distress in preterm or low birth weight infants is often treated with supplemental oxygen. However, this therapy can disrupt normal lung development and architecture and alter responses to respiratory insults. Similarly, exposure of newborn mice to 100% oxygen during saccular lung development leads to permanent alveolar simplification, and upon challenge with influenza A virus, mice exhibit reduced host resistance. Natural killer (NK) cells are key players in antiviral immunity, and emerging evidence suggest they also help to maintain homeostasis in peripheral tissues, including the lung, by promoting epithelial cell regeneration via IL-22. We tested the hypothesis that adult mice exposed to hyperoxia as neonates have modified NK cell responses to infection. We report here that mice exposed to neonatal hyperoxia had fewer IL-22(+) NK cells in their lungs after influenza virus challenge and a parallel increase in IFN-γ(+) NK cells. Using reciprocal bone marrow chimeric mice, we show that exposure of either hematopoietic or nonhematopoietic cells was sufficient to increase the severity of infection and to diminish the frequency of IL-22(+) NK cells in the infected lung. Overall, our findings suggest that neonatal hyperoxia leads to long-term changes in the reparative vs. cytotoxic nature of NK cells and that this is due in part to intrinsic changes in hematopoietic cells. These differences may contribute to how oxygen alters the host response to respiratory viral infections.

Activation of the aryl hydrocarbon receptor during development enhances the pulmonary CD4+ T-cell response to viral infection.

Respiratory infections are a threat to health and economies worldwide, yet the basis for striking variation in the severity of infection is not completely understood. Environmental exposures during development are associated with increased severity and incidence of respiratory infection later in life. Many of these exposures include ligands of the aryl hydrocarbon receptor (AHR), a transcription factor expressed by immune and nonimmune cells. In adult animals, AHR activation alters CD4(+) T cells and changes immunopathology. Developmental AHR activation impacts CD4(+) T-cell responses in lymphoid tissues, but whether skewed responses are also present in the infected lung is unknown. To determine whether pulmonary CD4(+) T-cell responses are modified by developmental AHR activation, mice were exposed to the prototypical AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin during development and infected with influenza virus as adults. Lungs of exposed offspring had greater bronchopulmonary inflammation compared with controls, and activated, virus-specific CD4(+) T cells contributed to the infiltrating leukocytes. These effects were CD4(+) T cell subset specific, with increases in T helper type 1 and regulatory T cells, but no change in the frequency of T helper type 17 cells in the infected lung. This is in direct contrast to prior reports of suppressed conventional CD4(+) T-cell responses in the lymph node. Using adoptive transfers and manipulating the pathogen properties, we determined that developmental exposure influenced factors intrinsic and extrinsic to CD4(+) T cells and may involve developmentally induced changes in signals from infected lung epithelial cells. Thus developmental exposures lead to context-dependent changes in pulmonary CD4(+) T-cell subsets, which may contribute to differential responses to respiratory infection.

Novel cellular targets of AhR underlie alterations in neutrophilic inflammation and inducible nitric oxide synthase expression during influenza virus infection.

The underlying reasons for variable clinical outcomes from respiratory viral infections remain uncertain. Several studies suggest that environmental factors contribute to this variation, but limited knowledge of cellular and molecular targets of these agents hampers our ability to quantify or modify their contribution to disease and improve public health. The aryl hydrocarbon receptor (AhR) is an environment-sensing transcription factor that binds many anthropogenic and natural chemicals. The immunomodulatory properties of AhR ligands are best characterized with extensive studies of changes in CD4(+) T cell responses. Yet, AhR modulates other aspects of immune function. We previously showed that during influenza virus infection, AhR activation modulates neutrophil accumulation in the lung, and this contributes to increased mortality in mice. Enhanced levels of inducible NO synthase (iNOS) in infected lungs are observed during the same time frame as AhR-mediated increased pulmonary neutrophilia. In this study, we evaluated whether these two consequences of AhR activation are causally linked. Reciprocal inhibition of AhR-mediated elevations in iNOS and pulmonary neutrophilia reveal that although they are contemporaneous, they are not causally related. We show using Cre/loxP technology that elevated iNOS levels and neutrophil number in the infected lung result from separate, AhR-dependent signaling in endothelial and respiratory epithelial cells, respectively. Studies using mutant mice further reveal that AhR-mediated alterations in these innate responses to infection require a functional nuclear localization signal and DNA binding domain. Thus, gene targets of AhR in non-hematopoietic cells are important new considerations for understanding AhR-mediated changes in innate anti-viral immunity.

Neonatal oxygen exposure alters airway hyper-responsiveness but not the response to allergen challenge in adult mice.

BACKGROUND: Infants born prematurely are often treated with supplemental oxygen, which can increase their risk for airway hyper-responsiveness (AHR), asthma, reduced lung function, and altered responses to respiratory viral infections later in childhood. Likewise, exposure of newborn mice to hyperoxia alters baseline pulmonary mechanics and the host response to influenza A virus infection in adult mice. Here, we use this mouse model to test the hypothesis that neonatal hyperoxia also promotes AHR and exacerbated allergen-induced symptoms in adult mice. METHODS: Baseline lung mechanics and AHR measured by methacholine provocation were assessed in adult male and female mice exposed to room air or 100% oxygen (hyperoxia) between post-natal days 0-4. AHR and lung inflammation were evaluated after adult female mice were sensitized with ovalbumin (OVA) plus alum and challenged with aerosolized OVA. RESULTS: Baseline lung compliance increased and resistance decreased in adult female, but not male, mice exposed to neonatal hyperoxia compared with siblings exposed to room air. Neonatal hyperoxia significantly enhanced methacholine-induced AHR in female mice, but did not affect allergen-induced AHR to methacholine or lung inflammation. CONCLUSION: Increased incidence of AHR and asthma is reported in children born prematurely and exposed to supplemental oxygen. Our findings in adult female mice exposed to hyperoxia as neonates suggest that this AHR reported in children born prematurely may reflect non-atopic wheezing due to intrinsic structural changes in airway development.

Binary and quaternary mixtures of perfluoroalkyl substances (PFAS) differentially affect the immune response to influenza A virus infection.

Per- and polyfluoroalkyl substances (PFAS) are anthropogenic organofluorine compounds that persist indefinitely in the environment and bioaccumulate throughout all trophic levels. Biomonitoring efforts have detected multiple PFAS in the serum of most people. Immune suppression has been among the most consistent effects of exposure to PFAS. PFAS often co-occur as mixtures in the environment, however, few studies have examined immunosuppression of PFAS mixtures or determined whether PFAS exposure affects immune function in the context of infection. In this study, mixtures containing two or four different PFAS and a mouse model of infection with influenza A virus (IAV) were used to assess immunotoxicity of PFAS mixtures. PFAS were administered via the drinking water as either a binary mixture of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) or quaternary mixture of PFOS, PFOA, perfluorohexane sulfonate (PFHxS), and perfluorononanoic acid (PFNA). The results indicated that the binary mixture affected the T-cell response, while the quaternary mixture affected the B-cell response to infection. These findings indicate that the immunomodulatory effects of PFAS mixtures are not simply additive, and that the sensitivity of immune responses to PFAS varies by cell type and mixture. The study also demonstrates the importance of studying adverse health effects of PFAS mixtures.

DMT1 knockout abolishes ferroptosis induced mitochondrial dysfunction in C. elegans amyloid ß proteotoxicity.

Iron is critical for neuronal activity and metabolism, and iron dysregulation alters these functions in age-related neurodegenerative disorders, such as Alzheimer's disease (AD). AD is a chronic neurodegenerative disease characterized by progressive neuronal dysfunction, memory loss and decreased cognitive function. AD patients exhibit elevated iron levels in the brain compared to age-matched non-AD individuals. However, the degree to which iron overload contributes to AD pathogenesis is unclear. Here, we evaluated the involvement of ferroptosis, an iron-dependent cell death process, in mediating AD-like pathologies in C. elegans. Results showed that iron accumulation occurred prior to the loss of neuronal function as worms age. In addition, energetic imbalance was an early event in iron-induced loss of neuronal function. Furthermore, the loss of neuronal function was, in part, due to increased mitochondrial reactive oxygen species mediated oxidative damage, ultimately resulting in ferroptotic cell death. The mitochondrial redox environment and ferroptosis were modulated by pharmacologic processes that exacerbate or abolish iron accumulation both in wild-type worms and worms with increased levels of neuronal amyloid beta (Aß). However, neuronal Aß worms were more sensitive to ferroptosis-mediated neuronal loss, and this increased toxicity was ameliorated by limiting the uptake of ferrous iron through knockout of divalent metal transporter 1 (DMT1). In addition, DMT1 knockout completely suppressed phenotypic measures of Aß toxicity with age. Overall, our findings suggest that iron-induced ferroptosis alters the mitochondrial redox environment to drive oxidative damage when neuronal Aß is overexpressed. DMT1 knockout abolishes neuronal Aß-associated pathologies by reducing neuronal iron uptake.

DMT1 knockout abolishes ferroptosis induced mitochondrial dysfunction in C. elegans amyloid ß proteotoxicity.

Iron is critical for neuronal activity and metabolism, and iron dysregulation alters these functions in age-related neurodegenerative disorders, such as Alzheimer's disease (AD). AD is a chronic neurodegenerative disease characterized by progressive neuronal dysfunction, memory loss and decreased cognitive function. AD patients exhibit elevated iron levels in the brain compared to age-matched non-AD individuals. However, the degree to which iron overload contributes to AD pathogenesis is unclear. Here, we evaluated the involvement of ferroptosis, an iron-dependent cell death process, in mediating AD-like pathologies in C. elegans. Results showed that iron accumulation occurred prior to the loss of neuronal function as worms age. In addition, energetic imbalance was an early event in iron-induced loss of neuronal function. Furthermore, the loss of neuronal function was, in part, due to increased mitochondrial reactive oxygen species mediated oxidative damage, ultimately resulting in ferroptotic cell death. The mitochondrial redox environment and ferroptosis were modulated by pharmacologic processes that exacerbate or abolish iron accumulation both in wild-type worms and worms with increased levels of neuronal amyloid beta (Aß). However, neuronal Aß worms were more sensitive to ferroptosis-mediated neuronal loss, and this increased toxicity was ameliorated by limiting the uptake of ferrous iron through knockout of divalent metal transporter 1 (DMT1). In addition, DMT1 knockout completely suppressed phenotypic measures of Aß toxicity with age. Overall, our findings suggest that iron-induced ferroptosis alters the mitochondrial redox environment to drive oxidative damage when neuronal Aß is overexpressed. DMT1 knockout abolishes neuronal Aß-associated pathologies by reducing neuronal iron uptake.

Neonatal hyperoxia increases sensitivity of adult mice to bleomycin-induced lung fibrosis.

Supplemental oxygen used to treat infants born prematurely constitutes a major risk factor for long-term deficits in lung function and host defense against respiratory infections. Likewise, neonatal oxygen exposure results in alveolar simplification in adult mice, and enhances leukocyte recruitment and fibrosis when adult mice are infected with a sublethal dose of influenza A virus. Because pulmonary fibrosis was not observed in infected adult mice exposed to room air as neonates, previous neonatal oxygen exposure may have reprogrammed how the adult lung responds to epithelial injury. By administering bleomycin to adult mice exposed to room air or hyperoxia as neonates, we tested the hypothesis that neonatal hyperoxia enhances fibrosis when the epithelium is injured by direct fibrotic stimulus. Increased sensitivity to bleomycin-induced lung fibrosis was observed in adult mice exposed to neonatal hyperoxia, and was associated with increased numbers of leukocytes and an accumulation of active transforming growth factor (TGF)-ß1 in the lung. Fate mapping of the respiratory epithelium revealed that the epithelial-mesenchymal transition was not a significant source of fibroblasts in room air-exposed or oxygen-exposed mice treated with bleomycin. Instead, the treatment of mice with anti-Gr-1 antibody that depletes neutrophils and myeloid-derived suppressor cells reduced the early activation of TGF-ß1 and attenuated hyperoxia-enhanced fibrosis. Because bleomycin and influenza A virus both cause epithelial injury, understanding how neonatal hyperoxia reprograms the epithelial response to these two different injurious agents could lead to new therapeutic opportunities for treating lung diseases attributed to prematurity.