LAUSR

Deficiency of acid sphingomyelinase (ASM) causes the lysosomal storage Niemann-Pick disease (NPD). NPD type B patients 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+/SiglecF+ 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, along with increased CD11c+/CD11b+ cells and > 2-fold increase in lung and plasma pro-inflammatory cytokines. Macrophages, neutrophils, eosinophils, and non-inflammatory lung cells of ASM-deficient lungs also exhibited marked accumulation of chitinase-like protein Ym1/2, that 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.