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Principal Investigator: Magdalena Maria Gorska
Organization: NATIONAL JEWISH HEALTH
Fiscal Year: 2024
Award: $610,821
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
A growing number of epidemiological studies link childhood asthma with maternal environmental exposures
with the strongest evidence provided for diesel exhaust and cigarette smoke. How maternal exposures lead to
asthma in offspring is unknown. To address this, we developed a mouse model of asthma susceptibility in pups
by exposing their mothers to diesel exhaust particles (DEP). Our data suggests that in this DEP-driven model,
asthma-predisposing information is transmitted in part by a subset of offspring long-term hematopoietic stem
cells (LT-HSCs), in the form of a stem cell memory. This subset distinguishes itself by expression of the IL3
receptor and is programmed for enhanced generation of basophils by the synergistic action of DEP-induced
IL1b and IL3. One key mechanism of the synergism between IL1b and IL3 is the ability of IL1b to increase
stem cell sensitivity to IL3 which is in part due to IL1b-mediated upregulation of IL3R b chain. In addition to
expanding the basophil lineage, IL3 and IL1b are likely to enhance its capacity to promote asthma. Previous
studies show that IL1b potentiates basophil histamine release and IL3 potently stimulates their IL4 production,
sowing the seed for type-2 immune response. Consistent with this, in DEP offspring, basophils overexpress
IL4. The IL3/IL1b-primed, expanded, IL4-overexpressing basophil population becomes a key driver of the type-
2 immune response and asthma upon allergen challenge. Basophil depletion in DEP pups prevents generation
of allergen-specific IgE and development of asthma. This is in contrast with data obtained in plain allergen-
based models in which basophils are redundant for production of IgE and asthma. Our overarching hypothesis
is that maternal exposure to DEP induces asthma susceptibility in offspring through IL1b and IL3 driven
programming of the hematopoietic stem cell-basophil axis. In Aim 1, by performing stem cell transplantation
experiments, we will establish links between DEP IL3R+ LT-HSCs, increased basopoiesis and predisposition to
asthma. We will define molecular basis of DEP IL3R+ LT-HSC programming by analyzing their transcriptomes
(RNA-seq) and chromatin remodeling at gene regulatory sites (ATAC-seq). In Aim 2 we will study importance
of IL1b and IL3 in programming of the HSC-basophil axis for asthma induction. In our model, IL1b and IL3 are
increased in offspring and maternal tissues, including maternal serum. We propose that maternal IL1b and IL3
are important at early stages of embryonic hematopoiesis, when HSCs undergo their initial divisions and
embryonic sources of IL1b and IL3 are scarce. Offspring-derived IL1b and IL3 complete the HSC programming
process, sustain basopoiesis at a high level, and contribute to basophil activation after maternal cytokines fade
away. To define how maternal IL1b and IL3 are transferred to embryos, study their roles and roles of offspring-
encoded IL1b and IL3, we will perform serum transfers, injections with radiolabeled cytokines, and combine
IL1b or IL3 KO strategies with embryo transfers. In Aim 3 we will use human blood samples to study IL1b and
IL3 guided basophil development in childhood asthma.
Terms: <0-11 years old><ATAC sequencing><ATAC-seq><ATACseq><Address><Allergens><Allergic><Assay for Transposase-Accessible Chromatin using sequencing><Asthma><Asthma in Children><B-Cell Stimulatory Factor 1 Gene><B220><BSF-1 Gene><BSF1 Gene><Basophilic Granulocyte><Basophils><Biological Markers><Blood Basophil><Blood Precursor Cell><Blood Sample><Blood Serum><Blood specimen><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><Bronchial Asthma><CD123><CD123 Antigen><CD45><Cell Body><Cell Lineage><Cells><Cells Placenta-Tissue><Child><Child Youth><Childhood Asthma><Children (0-21)><Chronic><Data><Development><Diesel Exhaust><Embryo><Embryo Transfer><Embryonic><Enhancers><Environment><Environmental Exposure><Eosinophil-Mast Cell Growth-Factor><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Erythrocyte Burst-Promoting Factor><Exposure to><Female><Future><GP180><Generations><Genes><HSC subsets><Hematopoiesis><Hematopoietic Cellular Control Mechanisms><Hematopoietic Cytokine><Hematopoietic Progenitor Cells><Hematopoietic Stem Cell subsets><Hematopoietic progenitor subsets><Hematopoietic stem cells><Histamine Liberation><Histamine Release><Human><IL-3><IL-3 Gene><IL-3 Receptors><IL-4 Gene><IL3><IL3 Gene><IL3 Protein><IL3 Receptors><IL3R><IL3RA><IL3RA gene><IL3RAX><IL3RX><IL4><IL4 gene><IgE><Immune response><Immune system><Immunoglobulin E><Immunological response><In Vitro><Injections><Interleukin 3 Receptor Alpha><Interleukin-3 Receptor><Interleukin-4 Gene><Interleukin-4 Precursor Gene><LY5><Lead><Link><Lymphoid Cell><Mast-Cell Colony-Stimulating Factor><Maternal Exposure><Measures><Mediating><Memory><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Mothers><Murine><Mus><Myeloid Cells><Normal Placentoma><Null Cells><Null Lymphocytes><P-CSF><P-Cell Stimulating Factor><PTPRC><PTPRC gene><Pathway interactions><Pb element><Pediatric asthma><Phenotype><Placenta><Placenta Embryonic Tissue><Placentome><Population><Predisposition><Preventative strategy><Prevention strategy><Preventive strategy><Process><Production><Progenitor Cell Transplantation><Progenitor Cells><RNA Seq><RNA sequencing><RNAseq><Radioactivity><Radiolabeled><Regulatory Element><Reporter><Reporting><Risk><Role><Serum><Site><Source><Stem Cell Transplantation><Stem cell transplant><Susceptibility><System><T200><Testing><Tissues><Transmission><Up-Regulation><Upregulation><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><asthma model><bio-markers><biologic marker><biomarker><blood cell formation><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><chromatin remodeling><cigarette smoke><congenic><cytokine><developmental><diagnostic approach><diagnostic strategy><early embryonic stage><embryo transplantation><epidemiologic investigation><epidemiology study><experiment><experimental research><experimental study><experiments><global gene expression><global transcription profile><heavy metal Pb><heavy metal lead><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><high risk><host response><immune system response><immunoresponse><imprint><indexing><kids><life span><lifespan><maternal serum><meeting><meetings><mouse model><murine model><new diagnostics><next generation diagnostics><novel diagnostics><offspring><overexpress><overexpression><particle><particle exposure><pathway><placental transfer><pregnant><prevent><preventing><progenitor transplantation><programs><promoter><promotor><pup><radioactivities><radiolabeling><radiologically labeled><self-renew><self-renewal><social role><stem and progenitor cell transplantations><stem cells><synergism><transcriptome><transcriptome sequencing><transcriptomic sequencing><transmission process><treatment strategy><youngster>