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Item Altered Macrophage Function Associated with Crystalline Lung Inflammation in Acid Sphingomyelinase Deficiency(American Thoracic Society, 2021) Poczobutt, Joanna M.; Mikosz, Andrew M.; Poirier, Christophe; Beatman, Erica L.; Serban, Karina A.; Gally, Fabienne; Cao, Danting; McCubbrey, Alexandra L.; Cornell, Christina F.; Schweitzer, Kelly S.; Berdyshev, Evgeny V.; Bronova, Irina A.; Paris, François; Petrache, Irina; Medicine, School of MedicineDeficiency of ASM (acid sphingomyelinase) causes the lysosomal storage Niemann-Pick disease (NPD). Patients with NPD type B may develop progressive interstitial lung disease with frequent respiratory infections. Although several investigations using the ASM-deficient (ASMKO) mouse NPD model revealed inflammation and foamy macrophages, there is little insight into the pathogenesis of NPD-associated lung disease. Using ASMKO mice, we report that ASM deficiency is associated with a complex inflammatory phenotype characterized by marked accumulation of monocyte-derived CD11b+ macrophages and expansion of airspace/alveolar CD11c+ CD11b− macrophages, both with increased size, granularity, and foaminess. Both the alternative and classical pathways were activated, with decreased in situ phagocytosis of opsonized (Fc-coated) targets, preserved clearance of apoptotic cells (efferocytosis), secretion of Th2 cytokines, increased CD11c+/CD11b+ cells, and more than a twofold increase in lung and plasma proinflammatory cytokines. Macrophages, neutrophils, eosinophils, and noninflammatory lung cells of ASMKO lungs also exhibited marked accumulation of chitinase-like protein Ym1/2, which formed large eosinophilic polygonal Charcot-Leyden–like crystals. In addition to providing insight into novel features of lung inflammation that may be associated with NPD, our report provides a novel connection between ASM and the development of crystal-associated lung inflammation with alterations in macrophage biology.Item Co-mobilization of CD11b/CD18 (Mac-1) and formyl peptide receptors (FPR) in human neutrophils(1993) Graves, Vicki L.Item The Complexity of Microglial Interactions With Innate and Adaptive Immune Cells in Alzheimer’s Disease(Frontiers Media, 2020-11-19) Wyatt-Johnson, Season K.; Brutkiewicz, Randy R.; Microbiology and Immunology, School of MedicineIn the naïve mouse brain, microglia and astrocytes are the most abundant immune cells; however, there is a complexity of other immune cells present including monocytes, neutrophils, and lymphocytic cells, such as natural killer (NK) cells, T cells, and B cells. In Alzheimer’s disease (AD), there is high inflammation, reactive microglia, and astrocytes, leaky blood–brain barrier, the buildup of amyloid-beta (Aβ) plaques, and neurofibrillary tangles which attract infiltrating peripheral immune cells that are interacting with the resident microglia. Limited studies have analyzed how these infiltrating immune cells contribute to the neuropathology of AD and even fewer have analyzed their interactions with the resident microglia. Understanding the complexity and dynamics of how these immune cells interact in AD will be important for identifying new and novel therapeutic targets. Thus, this review will focus on discussing our current understanding of how macrophages, neutrophils, NK cells, T cells, and B cells, alongside astrocytes, are altered in AD and what this means for the disorder, as well as how these cells are affected relative to the resident microglia.Item Engineering chimeric antigen receptor neutrophils from human pluripotent stem cells for targeted cancer immunotherapy(Cell Press, 2022) Chang, Yun; Syahirah, Ramizah; Wang, Xuepeng; Jin, Gyuhyung; Torregrosa-Allen, Sandra; Elzey, Bennett D.; Hummel, Sydney N.; Wang, Tianqi; Li, Can; Lian, Xiaojun; Deng, Qing; Broxmeyer, Hal E.; Bao, Xiaoping; Microbiology and Immunology, School of MedicineNeutrophils, the most abundant white blood cells in circulation, are closely related to cancer development and progression. Healthy primary neutrophils present potent cytotoxicity against various cancer cell lines through direct contact and via generation of reactive oxygen species. However, due to their short half-life and resistance to genetic modification, neutrophils have not yet been engineered with chimeric antigen receptors (CARs) to enhance their antitumor cytotoxicity for targeted immunotherapy. Here, we genetically engineered human pluripotent stem cells with synthetic CARs and differentiated them into functional neutrophils by implementing a chemically defined platform. The resulting CAR neutrophils present superior and specific cytotoxicity against tumor cells both in vitro and in vivo. Collectively, we established a robust platform for massive production of CAR neutrophils, paving the way to myeloid cell-based therapeutic strategies that would boost current cancer-treatment approaches.Item Evaluation of neutropenia and neutrophilia in preterm infants(Informa UK (Informa Healthcare), 2012-10) Nittala, Solomon; Subbarao, Girish C.; Maheshwari, Akhil; Department of Pediatrics, IU School of MedicineOBJECTIVE: Neutrophil counts are used routinely as part of the sepsis evaluation in newborn infants. In this article, we review the normal blood neutrophil concentrations and the clinical approach to neutropenia and neutrophilia in the neonatal period. METHODS: A literature search was performed using the databases PubMed, EMBASE, and Scopus, and the electronic archive of abstracts presented at the annual meetings of the Pediatric Academic Societies. RESULTS: Neutropenia and neutrophilia are documented frequently in premature infants. Neutropenia can be seen in up to 8% of all infants admitted to neonatal intensive care. Neutrophilia is even more common, reported in up to 40% of all preterm infants. CONCLUSIONS: Neutrophil counts should be carefully evaluated in premature neonates. Maternal and perinatal history, physical examination, and a limited laboratory assessment is usually adequate for making a diagnosis in most infants.Item Green tea catechin inhibits the activity and neutrophil release of Matrix Metalloproteinase-9.(Elsevier, 2016-10) Kim-Park, Wan K.; Allam, Eman S.; Palasuk, Jadesada; Kowolik, Michael; Park, Kichuel K.; Windsor, L. Jack; Department of Biomedical and Applied Sciences, IU School of DentistryGreen tea (Camellia sinensis; 綠茶 lǜ chá) extracts have been shown to possess anti-oxidant and anti-inflammatory effects in various cell types. Green tea extract (GTX) has been shown to significantly inhibit the activity of collagenase-3 (matrix metalloproteinase-13 (MMP-13)) in vitro. MMPs, such asItem Infiltration of inflammatory macrophages and neutrophils and widespread pyroptosis in lung drive influenza lethality in nonhuman primates(Public Library of Science, 2022-03-10) Corry, Jacqueline; Kettenburg, Gwenddolen; Upadhyay, Amit A.; Wallace, Megan; Marti, Michelle M.; Wonderlich, Elizabeth R.; Bissel, Stephanie J.; Goss, Kyndal; Sturgeon, Timothy J.; Watkins, Simon C.; Reed, Douglas S.; Bosinger, Steven E.; Barratt-Boyes, Simon M.; Medical and Molecular Genetics, School of MedicineSevere influenza kills tens of thousands of individuals each year, yet the mechanisms driving lethality in humans are poorly understood. Here we used a unique translational model of lethal H5N1 influenza in cynomolgus macaques that utilizes inhalation of small-particle virus aerosols to define mechanisms driving lethal disease. RNA sequencing of lung tissue revealed an intense interferon response within two days of infection that resulted in widespread expression of interferon-stimulated genes, including inflammatory cytokines and chemokines. Macaques with lethal disease had rapid and profound loss of alveolar macrophages (AMs) and infiltration of activated CCR2+ CX3CR1+ interstitial macrophages (IMs) and neutrophils into lungs. Parallel changes of AMs and neutrophils in bronchoalveolar lavage (BAL) correlated with virus load when compared to macaques with mild influenza. Both AMs and IMs in lethal influenza were M1-type inflammatory macrophages which expressed neutrophil chemotactic factors, while neutrophils expressed genes associated with activation and generation of neutrophil extracellular traps (NETs). NETs were prominent in lung and were found in alveolar spaces as well as lung parenchyma. Genes associated with pyroptosis but not apoptosis were increased in lung, and activated inflammatory caspases, IL-1β and cleaved gasdermin D (GSDMD) were present in bronchoalveolar lavage fluid and lung homogenates. Cleaved GSDMD was expressed by lung macrophages and alveolar epithelial cells which were present in large numbers in alveolar spaces, consistent with loss of epithelial integrity. Cleaved GSDMD colocalized with viral NP-expressing cells in alveoli, reflecting pyroptosis of infected cells. These novel findings reveal that a potent interferon and inflammatory cascade in lung associated with infiltration of inflammatory macrophages and neutrophils, elaboration of NETs and cell death by pyroptosis mediates lethal H5N1 influenza in nonhuman primates, and by extension humans. These innate pathways represent promising therapeutic targets to prevent severe influenza and potentially other primary viral pneumonias in humans.Item Neutrophil functional profiling and cytokine augmentation for patients with multiple recurrent infections: A case study(Elsevier, 2021) Alexander, Natalie J.; Bozym, David J.; Farmer, Joceyln R.; Parris, Priscilla; Viens, Adam; Atallah, Natalie; Hopke, Alex; Scherer, Allison; Dagher, Zeina; Barros, Nicolas; Knooihuizen, Sally A.I.; Saff, Sally Rebecca R.; Pasternack, Mark S.; Thompson, Ryan W.; Irimia, Daniel; Mansour, Michael K.; Medicine, School of MedicineItem Neutrophil transit time and sequestration in the upper lung(1992) Checkley, Lori Lynne