Poczobutt, Joanna M.Mikosz, Andrew M.Poirier, ChristopheBeatman, Erica L.Serban, Karina A.Gally, FabienneCao, DantingMcCubbrey, Alexandra L.Cornell, Christina F.Schweitzer, Kelly S.Berdyshev, Evgeny V.Bronova, Irina A.Paris, FrançoisPetrache, Irina2024-03-262024-03-262021Poczobutt JM, Mikosz AM, Poirier C, et al. Altered Macrophage Function Associated with Crystalline Lung Inflammation in Acid Sphingomyelinase Deficiency. Am J Respir Cell Mol Biol. 2021;64(5):629-640. doi:10.1165/rcmb.2020-0229OChttps://hdl.handle.net/1805/39537Deficiency 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.en-USPublisher PolicySphingomyelinaseMacrophagesChitinasesInflammationNeutrophilsArticle