Browsing by Author "Lajiness, Jacquelyn D."

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    Asthma, Allergy and Vitamin E: Current and Future Perspectives
    (Elsevier, 2022) Cook-Mills, Joan M.; Averill, Samantha H.; Lajiness, Jacquelyn D.; Pediatrics, School of Medicine
    Asthma and allergic disease result from interactions of environmental exposures and genetics. Vitamin E is one environmental factor that can modify development of allergy early in life and modify responses to allergen after allergen sensitization. Seemingly varied outcomes from vitamin E are consistent with the differential functions of the isoforms of vitamin E. Mechanistic studies demonstrate that the vitamin E isoforms α-tocopherol and γ-tocopherol have opposite functions in regulation of allergic inflammation and development of allergic disease, with α-tocopherol having anti-inflammatory functions and γ-tocopherol having pro-inflammatory functions in allergy and asthma. Moreover, global differences in prevalence of asthma by country may be a result, at least in part, of differences in consumption of these two isoforms of tocopherols. It is critical in clinical and animal studies that measurements of the isoforms of tocopherols be determined in vehicles for the treatments, and in the plasma and/or tissues before and after intervention. As allergic inflammation is modifiable by tocopherol isoforms, differential regulation by tocopherol isoforms provide a foundation for development of interventions to improve lung function in disease and raise the possibility of early life dietary interventions to limit the development of lung disease.
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    b-Glucosylceramides and Tocopherols Regulate Development and Function of Dendritic Cells
    (American Association of Immunologists, 2022-11-15) Lajiness, Jacquelyn D.; Amarsaikhan, Nansalmaa; Tat, Kiet; Tsoggerel, Angar; Cook-Mills, Joan M.; Microbiology and Immunology, School of Medicine
    In humans and mice, offspring of allergic mothers are predisposed to development of allergy. In mice, allergic mothers have elevated β-glucosylceramides (βGlcCers) that are transported to the fetus via the placenta and to offspring via milk. The elevated βGlcCers increase numbers of fetal liver CD11c+CD11b+ dendritic cells (DCs) and offspring allergen-induced lung eosinophilia. These effects are modifiable by maternal dietary supplementation with the plant-derived lipids α-tocopherol and γ-tocopherol. It is not known whether βGlcCers and tocopherols directly regulate development of DCs. In this study, we demonstrated that βGlcCers increased development of GM-CSF-stimulated mouse bone marrow-derived DCs (BMDCs) in vitro without altering expression of costimulatory molecules. This increase in BMDC numbers was blocked by α-tocopherol and potentiated by γ-tocopherol. Furthermore, βGlcCers increased PKCα and PKCδ activation in BMDCs that was blocked by α-tocopherol. In contrast, γ-tocopherol increased BMDC PKCα and PKCδ activation and enhanced the βGlcCer-induced increase in PKCδ activation in a DC subset. Antigen processing per DC was minimally enhanced in βGlcCer-treated BMDCs and not altered ex vivo in lung DCs from pups of allergic mothers. Pups of allergic mothers had an increased proportion of CD11b+CD11c+ subsets of DCs, contributing to enhanced stimulation of T cell proliferation ex vivo. Thus, βGlcCer, which is both necessary and sufficient for development of allergic predisposition in offspring of allergic mothers, directly increased development and PKC activation in BMDCs. Furthermore, this was modifiable by dietary tocopherols. This may inform design of future studies for the prevention or intervention in asthma and allergic disease.
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    Catching Our Breath: Updates on the Role of Dendritic Cell Subsets in Asthma
    (Wiley, 2023) Lajiness, Jacquelyn D.; Cook-Mills, Joan M.; Pediatrics, School of Medicine
    Dendritic cells (DCs), as potent antigen presenting cells, are known to play a central role in the pathophysiology of asthma. The understanding of DC biology has evolved over the years to include multiple subsets of DCs with distinct functions in the initiation and maintenance of asthma. Furthermore, asthma is increasingly recognized as a heterogeneous disease with potentially diverse underlying mechanisms. The goal of this review is to summarize the role of DCs and the various subsets therein in the pathophysiology of asthma and highlight some of the crucial animal models shaping the field today. Potential future avenues of investigation to address existing gaps in knowledge are discussed.
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    Origin, development, and differentiation of cardiac fibroblasts
    (Elsevier, 2014-05) Lajiness, Jacquelyn D.; Conway, Simon J.; Department of Pediatrics, IU School of Medicine
    Cardiac fibroblasts are the most abundant cell in the mammalian heart. While they have been historically underappreciated in terms of their functional contributions to cardiac development and physiology, they and their activated form, myofibroblasts, are now known to play key roles in both development and disease through structural, paracrine, and electrical interactions with cardiomyocytes. The lack of specific markers for fibroblasts currently convolutes the study of this dynamic cell lineage, but advances in marker analysis and lineage mapping technologies are continuously being made. Understanding how to best utilize these tools, both individually and in combination, will help to elucidate the functional significance of fibroblast-cardiomyocyte interactions in vivo. Here we review what is currently known about the diverse roles played by cardiac fibroblasts and myofibroblasts throughout development and periods of injury with the intent of emphasizing the duality of their nature.
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    A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas
    (Oxford University Press, 2019-02-15) Gehlhausen, Jeffrey R.; Hawley, Eric; Wahle, Benjamin Mark; He, Yongzheng; Edwards, Donna; Rhodes, Steven D.; Lajiness, Jacquelyn D.; Staser, Karl; Chen, Shi; Yang, Xianlin; Yuan, Jin; Li, Xiaohong; Jiang, Li; Smith, Abbi; Bessler, Waylan; Sandusky, George; Stemmer-Rachamimov, Anat; Stuhlmiller, Timothy J.; Angus, Steven P.; Johnson, Gary L.; Nalepa, Grzegorz; Yates, Charles W.; Clapp, D. Wade; Park, Su-Jung; Pediatrics, School of Medicine
    Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential.
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    SHP-2 deletion in postmigratory neural crest cells results in impaired cardiac sympathetic innervation
    (National Academy of Sciences, 2014-04-08) Lajiness, Jacquelyn D.; Snider, Paige; Wang, Jian; Feng, Gen-Sheng; Krenz, Maike; Conway, Simon J.; Department of Pediatrics, School of Medicine
    Autonomic innervation is an essential component of cardiovascular regulation that is first established from the neural crest (NC) lineage in utero and continues developing postnatally. Although in vitro studies have indicated that SH2-containing protein tyrosine phosphatase 2 (SHP-2) is a signaling factor critical for regulating sympathetic neuron differentiation, this has yet to be shown in the complex in vivo environment of cardiac autonomic innervation. Targeting SHP-2 within postmigratory NC lineages resulted in a fully penetrant mouse model of diminished sympathetic cardiac innervation and concomitant bradycardia. Immunohistochemistry of the sympathetic nerve marker tyrosine hydroxylase revealed a progressive loss of adrenergic ganglionic neurons and reduction of cardiac sympathetic axon density in Shp2 cKOs. Molecularly, Shp2 cKOs exhibit lineage-specific suppression of activated phospo-ERK1/2 signaling but not of other downstream targets of SHP-2 such as pAKT. Genetic restoration of the phosphorylated-extracellular signal-regulated kinase (pERK) deficiency via lineage-specific expression of constitutively active MEK1 was sufficient to rescue the sympathetic innervation deficit and its physiological consequences. These data indicate that SHP-2 signaling specifically through pERK in postmigratory NC lineages is essential for development and maintenance of sympathetic cardiac innervation postnatally.
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    Shp2 deletion in post-migratory neural crest cells results in impaired cardiac sympathetic innervation
    (2014-05) Lajiness, Jacquelyn D.; Ingram, David A., Jr.; Harrington, Maureen A.; Mirmira, Raghavendra G.; Payne, Mark; Rubart, Michael
    Autonomic innervation of the heart begins in utero and continues during the neonatal phase of life. A balance between the sympathetic and parasympathetic arms of the autonomic nervous system is required to regulate heart rate as well as the force of each contraction. Our lab studies the development of sympathetic innervation of the early postnatal heart in a conditional knockout (cKO) of Src homology protein tyrosine phosphatase 2 (Shp2). Shp2 is a ubiquitously expressed non-receptor phosphatase involved in a variety of cellular functions including survival, proliferation, and differentiation. We targeted Shp2 in post-migratory neural crest (NC) lineages using our novel Periostin-Cre. This resulted in a fully penetrant mouse model of diminished cardiac sympathetic innervation and concomitant bradycardia that progressively worsen. Shp2 is thought to mediate its basic cellular functions through a plethora of signaling cascades including extracellular signal-regulated kinases (ERK) 1 and 2. We hypothesize that abrogation of downstream ERK1/2 signaling in NC lineages is primarily responsible for the failed sympathetic innervation phenotype observed in our mouse model. Shp2 cKOs are indistinguishable from control littermates at birth and exhibit no gross structural cardiac anomalies; however, in vivo electrocardiogram (ECG) characterization revealed sinus bradycardia that develops as the Shp2 cKO ages. Significantly, 100% of Shp2 cKOs die within 3 weeks after birth. Characterization of the expression pattern of the sympathetic nerve marker tyrosine hydroxylase (TH) revealed a loss of functional sympathetic ganglionic neurons and reduction of cardiac sympathetic axon density in Shp2 cKOs. Shp2 cKOs exhibit lineage-specific suppression of activated pERK1/2 signaling, but not of other downstream targets of Shp2 such as pAKT (phosphorylated-Protein kinase B). Interestingly, restoration of pERK signaling via lineage-specific expression of constitutively active MEK1 (Mitogen-activated protein kinase kinase1) rescued TH-positive cardiac innervation as well as heart rate. These data suggest that the diminished sympathetic cardiac innervation and the resulting ECG abnormalities are a result of decreased pERK signaling in post-migratory NC lineages.
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    β-Glucosylceramides and Tocopherols Regulate Development and Function of Dendritic Cells
    (American Association of Immunologists, 2022) Lajiness, Jacquelyn D.; Amarsaikhan, Nansalmaa; Tat, Kiet; Tsoggerel, Angar; Cook-Mills, Joan M.; Pediatrics, School of Medicine
    In humans and mice, offspring of allergic mothers are predisposed to development of allergy. In mice, allergic mothers have elevated β-glucosylceramides (βGlcCers) that are transported to the fetus via the placenta and to offspring via milk. The elevated βGlcCers increase numbers of fetal liver CD11c+CD11b+ dendritic cells (DCs) and offspring allergen-induced lung eosinophilia. These effects are modifiable by maternal dietary supplementation with the plant-derived lipids α-tocopherol and γ-tocopherol. It is not known whether βGlcCers and tocopherols directly regulate development of DCs. In this study, we demonstrated that βGlcCers increased development of GM-CSF-stimulated mouse bone marrow-derived DCs (BMDCs) in vitro without altering expression of costimulatory molecules. This increase in BMDC numbers was blocked by α-tocopherol and potentiated by γ-tocopherol. Furthermore, βGlcCers increased PKCα and PKCδ activation in BMDCs that was blocked by α-tocopherol. In contrast, γ-tocopherol increased BMDC PKCα and PKCδ activation and enhanced the βGlcCer-induced increase in PKCδ activation in a DC subset. Antigen processing per DC was minimally enhanced in βGlcCer-treated BMDCs and not altered ex vivo in lung DCs from pups of allergic mothers. Pups of allergic mothers had an increased proportion of CD11b+CD11c+ subsets of DCs, contributing to enhanced stimulation of T cell proliferation ex vivo. Thus, βGlcCer, which is both necessary and sufficient for development of allergic predisposition in offspring of allergic mothers, directly increased development and PKC activation in BMDCs. Furthermore, this was modifiable by dietary tocopherols. This may inform design of future studies for the prevention or intervention in asthma and allergic disease.