RESUMEN
Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Molecular analyses of human and murine samples define microenvironmental consequences of obesity that foster tumorigenesis rather than new driver gene mutations, including significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta cell expression of the peptide hormone cholecystokinin (Cck) in response to obesity and show that islet Cck promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment and implicate endocrine-exocrine signaling beyond insulin in PDAC development.
Asunto(s)
Carcinoma Ductal Pancreático/etiología , Carcinoma Ductal Pancreático/metabolismo , Obesidad/metabolismo , Animales , Carcinogénesis/genética , Carcinoma Ductal Pancreático/patología , Línea Celular , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Células Endocrinas/metabolismo , Glándulas Exocrinas/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación/genética , Obesidad/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Transducción de Señal/genética , Microambiente Tumoral/fisiología , Neoplasias PancreáticasRESUMEN
Memory B cells (MBCs) are key providers of long-lived immunity against infectious disease, yet in chronic viral infection, they do not produce effective protection. How chronic viral infection disrupts MBC development and whether such changes are reversible remain unknown. Through single-cell (sc)ATAC-seq and scRNA-seq during acute versus chronic lymphocytic choriomeningitis viral infection, we identified a memory subset enriched for interferon (IFN)-stimulated genes (ISGs) during chronic infection that was distinct from the T-bet+ subset normally associated with chronic infection. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic MBCs, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing phenotypic changes in the dominating MBC subset, with a decrease in the ISG subset and an increase in CD11c+CD80+ cells. However, timing was critical, with MBCs resistant to intervention at 4 weeks post-infection. Together, our research identifies a key mechanism to instruct MBC identity during viral infection.
Asunto(s)
Epigénesis Genética , Interferón Tipo I , Coriomeningitis Linfocítica , Virus de la Coriomeningitis Linfocítica , Células B de Memoria , Animales , Interferón Tipo I/metabolismo , Interferón Tipo I/inmunología , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/virología , Ratones , Virus de la Coriomeningitis Linfocítica/inmunología , Células B de Memoria/inmunología , Ratones Endogámicos C57BL , Receptor de Interferón alfa y beta/genética , Memoria Inmunológica/inmunología , Enfermedad Crónica , Subgrupos de Linfocitos B/inmunología , Análisis de la Célula IndividualRESUMEN
CD8+ T cells responding to chronic infections or tumors acquire an 'exhausted' state associated with elevated expression of inhibitory receptors, including PD-1, and impaired cytokine production. Exhausted T cells are continuously replenished by T cells with precursor characteristics that self-renew and depend on the transcription factor TCF1; however, their developmental requirements are poorly understood. In the present study, we demonstrate that high antigen load promoted the differentiation of precursor T cells, which acquired hallmarks of exhaustion within days of infection, whereas early effector cells retained polyfunctional features. Early precursor T cells showed epigenetic imprinting characteristic of T cell receptor-dependent transcription factor binding and were restricted to the generation of cells displaying exhaustion characteristics. Transcription factors BACH2 and BATF were key regulators with opposing functions in the generation of early precursor T cells. Overall, we demonstrate that exhaustion manifests first in TCF1+ precursor T cells and is propagated subsequently to the pool of antigen-specific T cells.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Células Precursoras de Linfocitos T/inmunología , Animales , Diferenciación Celular , Autorrenovación de las Células , Células Cultivadas , Enfermedad Crónica , Anergia Clonal , Epigénesis Genética , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Tolerancia Inmunológica , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/metabolismo , Especificidad del Receptor de Antígeno de Linfocitos TRESUMEN
Despite evidence of chronic inflammation in myelodysplastic syndrome (MDS) and cell-intrinsic dysregulation of Toll-like receptor (TLR) signaling in MDS hematopoietic stem and progenitor cells (HSPCs), the mechanisms responsible for the competitive advantage of MDS HSPCs in an inflammatory milieu over normal HSPCs remain poorly defined. Here, we found that chronic inflammation was a determinant for the competitive advantage of MDS HSPCs and for disease progression. The cell-intrinsic response of MDS HSPCs, which involves signaling through the noncanonical NF-κB pathway, protected these cells from chronic inflammation as compared to normal HSPCs. In response to inflammation, MDS HSPCs switched from canonical to noncanonical NF-κB signaling, a process that was dependent on TLR-TRAF6-mediated activation of A20. The competitive advantage of TLR-TRAF6-primed HSPCs could be restored by deletion of A20 or inhibition of the noncanonical NF-κB pathway. These findings uncover the mechanistic basis for the clonal dominance of MDS HSPCs and indicate that interfering with noncanonical NF-κB signaling could prevent MDS progression.
Asunto(s)
Células Madre Hematopoyéticas/fisiología , Inflamación/inmunología , Síndromes Mielodisplásicos/inmunología , FN-kappa B/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , Anciano , Animales , Diferenciación Celular , Células Cultivadas , Humanos , Masculino , Ratones , Ratones Transgénicos , Mielopoyesis , FN-kappa B/genética , Transducción de Señal , Factor 6 Asociado a Receptor de TNF/genética , Receptores Toll-Like/metabolismo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
T cell factor 1 (Tcf-1) expressing CD8+ T cells exhibit stem-like self-renewing capacity, rendering them key for immune defense against chronic viral infection and cancer. Yet, the signals that promote the formation and maintenance of these stem-like CD8+ T cells (CD8+SL) remain poorly defined. Studying CD8+ T cell differentiation in mice with chronic viral infection, we identified the alarmin interleukin-33 (IL-33) as pivotal for the expansion and stem-like functioning of CD8+SL as well as for virus control. IL-33 receptor (ST2)-deficient CD8+ T cells exhibited biased end differentiation and premature loss of Tcf-1. ST2-deficient CD8+SL responses were restored by blockade of type I interferon signaling, suggesting that IL-33 balances IFN-I effects to control CD8+SL formation in chronic infection. IL-33 signals broadly augmented chromatin accessibility in CD8+SL and determined these cells' re-expansion potential. Our study identifies the IL-33-ST2 axis as an important CD8+SL-promoting pathway in the context of chronic viral infection.
Asunto(s)
Linfocitos T CD8-positivos , Interleucina-33 , Coriomeningitis Linfocítica , Animales , Ratones , Alarminas/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica , Ratones Endogámicos C57BL , Infección Persistente , Factor 1 de Transcripción de Linfocitos T/metabolismoRESUMEN
Despite intense interest in antiviral T cell priming, the routes by which virions move in lymph nodes (LNs) are imperfectly understood. Current models fail to explain how virus-infected cells rapidly appear within the LN interior after viral infection. To better understand virion trafficking in the LN, we determined the locations of virions and infected cells after administration to mice of vaccinia virus or Zika virus. Notably, many rapidly infected cells in the LN interior were adjacent to LN conduits. Through the use of confocal and electron microscopy, we clearly visualized virions within conduits. Functionally, CD8+ T cells rapidly and preferentially associated with vaccinia virus-infected cells in the LN paracortex, which led to T cell activation in the LN interior. These results reveal that it is possible for even large virions to flow through LN conduits and infect dendritic cells within the T cell zone to prime CD8+ T cells.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Ganglios Linfáticos/inmunología , Activación de Linfocitos/inmunología , Virión/inmunología , Animales , Linfocitos T CD8-positivos/virología , Femenino , Ganglios Linfáticos/ultraestructura , Ganglios Linfáticos/virología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microscopía Confocal , Microscopía Electrónica de Transmisión , Virus Vaccinia/inmunología , Virus Vaccinia/fisiología , Virión/fisiología , Virión/ultraestructura , Virosis/inmunología , Virosis/virología , Virus Zika/inmunología , Virus Zika/fisiologíaRESUMEN
The transcription factor interferon regulatory factor 2 (IRF2) translates interferon signaling to regulate T cells. In this issue of Immunity, Lukhele et al. identify IRF2 in tumor-infiltrating T cells as a sensor for extrinsic signals that drives an exhaustion program.
Asunto(s)
Agotamiento de Células T , Factores de Transcripción , Factor 2 Regulador del Interferón/genética , Factor 2 Regulador del Interferón/metabolismo , Regulación de la Expresión GénicaRESUMEN
Obesity leads to chronic, systemic inflammation and can lead to insulin resistance (IR), ß-cell dysfunction, and ultimately type 2 diabetes (T2D). This chronic inflammatory state contributes to long-term complications of diabetes, including non-alcoholic fatty liver disease (NAFLD), retinopathy, cardiovascular disease, and nephropathy, and may underlie the association of type 2 diabetes with other conditions such as Alzheimer's disease, polycystic ovarian syndrome, gout, and rheumatoid arthritis. Here, we review the current understanding of the mechanisms underlying inflammation in obesity, T2D, and related disorders. We discuss how chronic tissue inflammation results in IR, impaired insulin secretion, glucose intolerance, and T2D and review the effect of inflammation on diabetic complications and on the relationship between T2D and other pathologies. In this context, we discuss current therapeutic options for the treatment of metabolic disease, advances in the clinic and the potential of immune-modulatory approaches.
Asunto(s)
Complicaciones de la Diabetes/inmunología , Diabetes Mellitus Tipo 2/inmunología , Inflamación/inmunología , Obesidad/inmunología , Animales , Humanos , Inmunomodulación , Resistencia a la InsulinaRESUMEN
Reinvigoration of exhausted CD8+ T (Tex) cells by checkpoint immunotherapy depends on the activation of precursors of exhausted T (Tpex) cells, but the local anatomical context of their maintenance, differentiation, and interplay with other cells is not well understood. Here, we identified transcriptionally distinct Tpex subpopulations, mapped their differentiation trajectories via transitory cellular states toward Tex cells, and localized these cell states to specific splenic niches. Conventional dendritic cells (cDCs) were critical for successful αPD-L1 therapy and were required to mediate viral control. cDC1s were dispensable for Tpex cell expansion but provided an essential niche to promote Tpex cell maintenance, preventing their overactivation and T-cell-mediated immunopathology. Mechanistically, cDC1s insulated Tpex cells via MHC-I-dependent interactions to prevent their activation within other inflammatory environments that further aggravated their exhaustion. Our findings reveal that cDC1s maintain and safeguard Tpex cells within distinct anatomical niches to balance viral control, exhaustion, and immunopathology.
Asunto(s)
Linfocitos T CD8-positivos , Células Dendríticas , Diferenciación Celular , Inmunoterapia , Recuento de LinfocitosRESUMEN
RIG-I is essential for host defense against viral pathogens, as it triggers the release of type I interferons upon encounter with viral RNA molecules. In this study, we show that RIG-I is rapidly and efficiently activated by small quantities of incoming viral RNA and that it relies exclusively on the constitutively expressed resident pool of RIG-I receptors for a strong antiviral response. Live-cell imaging of RIG-I following stimulation with viral or synthetic dsRNA reveals that RIG-I signaling occurs without mass aggregation at the mitochondrial membrane. By contrast, interferon-induced RIG-I protein becomes embedded in cytosolic aggregates that are functionally unrelated to signaling. These findings suggest that endogenous RIG-I efficiently recognizes viral RNA and rapidly relays an antiviral signal to MAVS via a transient signaling complex and that cellular aggregates of RIG-I have a function that is distinct from signaling.
Asunto(s)
Interferón Tipo I , Transducción de Señal , Transducción de Señal/genética , Proteína 58 DEAD Box/genética , Proteína 58 DEAD Box/metabolismo , Antivirales/farmacología , Interferón Tipo I/genética , ARN Bicatenario/genética , ARN Viral/genética , Inmunidad InnataRESUMEN
The oropharyngeal mucosa serves as a perpetual pathogen entry point and a critical site for viral replication and spread. Here, we demonstrate that type 1 innate lymphoid cells (ILC1s) were the major immune force providing early protection during acute oral mucosal viral infection. Using intravital microscopy, we show that ILC1s populated and patrolled the uninfected labial mucosa. ILC1s produced interferon-γ (IFN-γ) in the absence of infection, leading to the upregulation of key antiviral genes, which were downregulated in uninfected animals upon genetic ablation of ILC1s or antibody-based neutralization of IFN-γ. Thus, tonic IFN-γ production generates increased oral mucosal viral resistance even before infection. Our results demonstrate barrier-tissue protection through tissue surveillance in the absence of rearranged-antigen receptors and the induction of an antiviral state during homeostasis. This aspect of ILC1 biology raises the possibility that these cells do not share true functional redundancy with other tissue-resident lymphocytes.
Asunto(s)
Interferón gamma/metabolismo , Linfocitos/inmunología , Orofaringe/inmunología , Mucosa Respiratoria/inmunología , Virus Vaccinia/fisiología , Vaccinia/inmunología , Animales , Células Cultivadas , Resistencia a la Enfermedad , Humanos , Inmunidad Innata , Interferón gamma/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Dominio T Box/genética , Células TH1/inmunologíaRESUMEN
Antigen-specific CD8+ T cells in chronic viral infections and tumors functionally deteriorate, a process known as exhaustion. Exhausted T cells are sustained by precursors of exhausted (Tpex) cells that self-renew while continuously generating exhausted effector (Tex) cells. However, it remains unknown how Tpex cells maintain their functionality. Here, we demonstrate that Tpex cells sustained mitochondrial fitness, including high spare respiratory capacity, while Tex cells deteriorated metabolically over time. Tpex cells showed early suppression of mTOR kinase signaling but retained the ability to activate this pathway in response to antigen receptor signals. Early transient mTOR inhibition improved long-term T cell responses and checkpoint inhibition. Transforming growth factor-ß repressed mTOR signaling in exhausted T cells and was a critical determinant of Tpex cell metabolism and function. Overall, we demonstrate that the preservation of cellular metabolism allows Tpex cells to retain long-term functionality to sustain T cell responses during chronic infection.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Metabolismo Energético/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias/metabolismo , Transducción de Señal/inmunologíaRESUMEN
Understanding the factors governing the stability of fault slip is a crucial problem in fault mechanics1-3. The importance of fault geometry and roughness on fault-slip behaviour has been highlighted in recent lab experiments4-7 and numerical models8-11, and emerging evidence suggests that large-scale complexities in fault networks have a vital role in the fault-rupture process12-18. Here we present a new perspective on fault creep by investigating the link between fault-network geometry and surface creep rates in California, USA. Our analysis reveals that fault groups exhibiting creeping behaviour show smaller misalignment in their fault-network geometry. The observation indicates that the surface fault traces of creeping regions tend to be simple, whereas locked regions tend to be more complex. We propose that the presence of complex fault-network geometries results in geometric locking that promotes stick-slip behaviour characterized by earthquakes, whereas simpler geometries facilitate smooth fault creep. Our findings challenge traditional hypotheses on the physical origins of fault creep explained primarily in terms of fault friction19-21 and demonstrate the potential for a new framework in which large-scale earthquake frictional behaviour is determined by a combination of geometric factors and rheological yielding properties.
RESUMEN
The deleterious effect of chronic activation of the IL-1ß system on type 2 diabetes and other metabolic diseases is well documented. However, a possible physiological role for IL-1ß in glucose metabolism has remained unexplored. Here we found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL-1ß, in a glucose-dependent manner. Subsequently, IL-1ß contributed to the postprandial stimulation of insulin secretion. Accordingly, lack of endogenous IL-1ß signaling in mice during refeeding and obesity diminished the concentration of insulin in plasma. IL-1ß and insulin increased the uptake of glucose into macrophages, and insulin reinforced a pro-inflammatory pattern via the insulin receptor, glucose metabolism, production of reactive oxygen species, and secretion of IL-1ß mediated by the NLRP3 inflammasome. Postprandial inflammation might be limited by normalization of glycemia, since it was prevented by inhibition of the sodium-glucose cotransporter SGLT2. Our findings identify a physiological role for IL-1ß and insulin in the regulation of both metabolism and immunity.
Asunto(s)
Diabetes Mellitus Tipo 2/inmunología , Inflamación/inmunología , Células Secretoras de Insulina/fisiología , Interleucina-1beta/metabolismo , Macrófagos/fisiología , Animales , Células Cultivadas , Glucosa/metabolismo , Humanos , Inflamasomas/metabolismo , Insulina/metabolismo , Interleucina-1beta/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Periodo Posprandial , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Transportador 2 de Sodio-Glucosa/metabolismoRESUMEN
Toll-like receptor (TLR) activation contributes to premalignant hematologic conditions, such as myelodysplastic syndromes (MDS). TRAF6, a TLR effector with ubiquitin (Ub) ligase activity, is overexpressed in MDS hematopoietic stem/progenitor cells (HSPCs). We found that TRAF6 overexpression in mouse HSPC results in impaired hematopoiesis and bone marrow failure. Using a global Ub screen, we identified hnRNPA1, an RNA-binding protein and auxiliary splicing factor, as a substrate of TRAF6. TRAF6 ubiquitination of hnRNPA1 regulated alternative splicing of Arhgap1, which resulted in activation of the GTP-binding Rho family protein Cdc42 and accounted for hematopoietic defects in TRAF6-expressing HSPCs. These results implicate Ub signaling in coordinating RNA processing by TLR pathways during an immune response and in premalignant hematologic diseases, such as MDS.
Asunto(s)
Células Madre Hematopoyéticas/fisiología , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Síndromes Mielodisplásicos/inmunología , Lesiones Precancerosas/inmunología , Transducción de Señal , Factor 6 Asociado a Receptor de TNF/metabolismo , Ubiquitinación , Animales , Autoinmunidad , Células Cultivadas , Hematopoyesis/genética , Ribonucleoproteína Nuclear Heterogénea A1 , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Inmunidad Innata , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Transducción de Señal/genética , Factor 6 Asociado a Receptor de TNF/genética , Receptores Toll-Like/metabolismo , Ubiquitinación/genética , Proteína de Unión al GTP cdc42/metabolismoRESUMEN
Anecdotal evidence indicates that people believe that morality is declining1,2. In a series of studies using both archival and original data (n = 12,492,983), we show that people in at least 60 nations around the world believe that morality is declining, that they have believed this for at least 70 years and that they attribute this decline both to the decreasing morality of individuals as they age and to the decreasing morality of successive generations. Next, we show that people's reports of the morality of their contemporaries have not declined over time, suggesting that the perception of moral decline is an illusion. Finally, we show how a simple mechanism based on two well-established psychological phenomena (biased exposure to information and biased memory for information) can produce an illusion of moral decline, and we report studies that confirm two of its predictions about the circumstances under which the perception of moral decline is attenuated, eliminated or reversed (that is, when respondents are asked about the morality of people they know well or people who lived before the respondent was born). Together, our studies show that the perception of moral decline is pervasive, perdurable, unfounded and easily produced. This illusion has implications for research on the misallocation of scarce resources3, the underuse of social support4 and social influence5.
Asunto(s)
Cultura , Ilusiones , Principios Morales , Humanos , Ilusiones/psicología , Relaciones Intergeneracionales , Envejecimiento/psicología , Sesgo , Sesgo Atencional , Apoyo Social/psicología , Influencia de los CompañerosRESUMEN
Neuronal activity is crucial for adaptive circuit remodelling but poses an inherent risk to the stability of the genome across the long lifespan of postmitotic neurons1-5. Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damaging stimuli during periods of heightened activity is unknown. Here we identify an activity-dependent DNA repair mechanism in which a new form of the NuA4-TIP60 chromatin modifier assembles in activated neurons around the inducible, neuronal-specific transcription factor NPAS4. We purify this complex from the brain and demonstrate its functions in eliciting activity-dependent changes to neuronal transcriptomes and circuitry. By characterizing the landscape of activity-induced DNA double-strand breaks in the brain, we show that NPAS4-NuA4 binds to recurrently damaged regulatory elements and recruits additional DNA repair machinery to stimulate their repair. Gene regulatory elements bound by NPAS4-NuA4 are partially protected against age-dependent accumulation of somatic mutations. Impaired NPAS4-NuA4 signalling leads to a cascade of cellular defects, including dysregulated activity-dependent transcriptional responses, loss of control over neuronal inhibition and genome instability, which all culminate to reduce organismal lifespan. In addition, mutations in several components of the NuA4 complex are reported to lead to neurodevelopmental and autism spectrum disorders. Together, these findings identify a neuronal-specific complex that couples neuronal activity directly to genome preservation, the disruption of which may contribute to developmental disorders, neurodegeneration and ageing.
Asunto(s)
Encéfalo , Reparación del ADN , Complejos Multiproteicos , Neuronas , Sinapsis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Encéfalo/metabolismo , Roturas del ADN de Doble Cadena , Regulación de la Expresión Génica , Lisina Acetiltransferasa 5/metabolismo , Complejos Multiproteicos/metabolismo , Neuronas/metabolismo , Sinapsis/metabolismo , Mutación , Longevidad/genética , Genoma , Envejecimiento/genética , Enfermedades NeurodegenerativasRESUMEN
Speciation leads to adaptive changes in organ cellular physiology and creates challenges for studying rare cell-type functions that diverge between humans and mice. Rare cystic fibrosis transmembrane conductance regulator (CFTR)-rich pulmonary ionocytes exist throughout the cartilaginous airways of humans1,2, but limited presence and divergent biology in the proximal trachea of mice has prevented the use of traditional transgenic models to elucidate ionocyte functions in the airway. Here we describe the creation and use of conditional genetic ferret models to dissect pulmonary ionocyte biology and function by enabling ionocyte lineage tracing (FOXI1-CreERT2::ROSA-TG), ionocyte ablation (FOXI1-KO) and ionocyte-specific deletion of CFTR (FOXI1-CreERT2::CFTRL/L). By comparing these models with cystic fibrosis ferrets3,4, we demonstrate that ionocytes control airway surface liquid absorption, secretion, pH and mucus viscosity-leading to reduced airway surface liquid volume and impaired mucociliary clearance in cystic fibrosis, FOXI1-KO and FOXI1-CreERT2::CFTRL/L ferrets. These processes are regulated by CFTR-dependent ionocyte transport of Cl- and HCO3-. Single-cell transcriptomics and in vivo lineage tracing revealed three subtypes of pulmonary ionocytes and a FOXI1-lineage common rare cell progenitor for ionocytes, tuft cells and neuroendocrine cells during airway development. Thus, rare pulmonary ionocytes perform critical CFTR-dependent functions in the proximal airway that are hallmark features of cystic fibrosis airway disease. These studies provide a road map for using conditional genetics in the first non-rodent mammal to address gene function, cell biology and disease processes that have greater evolutionary conservation between humans and ferrets.
Asunto(s)
Fibrosis Quística , Modelos Animales de Enfermedad , Hurones , Pulmón , Transgenes , Animales , Humanos , Animales Modificados Genéticamente , Linaje de la Célula , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Fibrosis Quística/patología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Hurones/genética , Hurones/fisiología , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Pulmón/citología , Pulmón/metabolismo , Pulmón/patología , Tráquea/citología , Transgenes/genéticaRESUMEN
A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 µm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1ß. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for PM2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.
Asunto(s)
Adenocarcinoma del Pulmón , Contaminantes Atmosféricos , Contaminación del Aire , Transformación Celular Neoplásica , Neoplasias Pulmonares , Animales , Ratones , Adenocarcinoma del Pulmón/inducido químicamente , Adenocarcinoma del Pulmón/genética , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/genética , Exposición a Riesgos Ambientales , Receptores ErbB/genética , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Material Particulado/efectos adversos , Material Particulado/análisis , Tamaño de la Partícula , Estudios de Cohortes , Macrófagos Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/patologíaRESUMEN
The respiratory endoderm develops from a small cluster of cells located on the ventral anterior foregut. This population of progenitors generates the myriad epithelial lineages required for proper lung function in adults through a complex and delicately balanced series of developmental events controlled by many critical signaling and transcription factor pathways. In the past decade, understanding of this process has grown enormously, helped in part by cell lineage fate analysis and deep sequencing of the transcriptomes of various progenitors and differentiated cell types. This review explores how these new techniques, coupled with more traditional approaches, have provided a detailed picture of development of the epithelial lineages in the lung and insight into how aberrant development can lead to lung disease.