Altered Macrophage Function Associated with Crystalline Lung Inflammation in Acid Sphingomyelinase Deficiency
| Autor: | Erica L. Beatman, Christophe Poirier, Danting Cao, Andrew M. Mikosz, Alexandra L. McCubbrey, Irina Petrache, Irina Bronova, Christina F Cornell, Evgeny Berdyshev, Joanna M Poczobutt, Karina A. Serban, Fabienne Gally, François Paris, Kelly S. Schweitzer |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Neutrophils Clinical Biochemistry Gene Expression Mice Lectins hemic and lymphatic diseases Macrophage Lung Th1-Th2 Balance Original Research Mice Knockout CD11b Antigen Chemistry Chitinases Interstitial lung disease Niemann-Pick Disease Type B Niemann-Pick Disease Type A respiratory system beta-N-Acetylhexosaminidases Sphingomyelin Phosphodiesterase medicine.anatomical_structure Female Acid sphingomyelinase medicine.symptom Lysophospholipase Sphingomyelin medicine.drug Pulmonary and Respiratory Medicine Inflammation Phagocytosis Macrophages Alveolar medicine Animals Humans Molecular Biology Cell Size Glycoproteins CD11 Antigens Macrophages nutritional and metabolic diseases Pneumonia Cell Biology medicine.disease respiratory tract diseases Eosinophils Disease Models Animal Cancer research Function (biology) |
| Zdroj: | Am J Respir Cell Mol Biol |
| ISSN: | 1535-4989 1044-1549 |
| DOI: | 10.1165/rcmb.2020-0229oc |
| Popis: | Deficiency 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. |
| Databáze: | OpenAIRE |
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