A Critical Role for ABCG1 in Macrophage Inflammation and Lung Homeostasis

Abstract

ATP-binding cassette transporter G1 (ABCG1) effluxes cholesterol from macrophages and plays an important role in pulmonary lipid homeostasis. We hypothesize that macrophages from Abcg1−/− mice have increased inflammatory activity, thereby promoting acceleration of pulmonary disease. We herein demonstrate increased numbers of inflammatory cytokines and infiltrating neutrophils, eosinophils, dendritic cells, T cells, and B cells into lungs of Abcg1−/− mice before the onset of severe lipidosis. We further investigated the role of macrophages in causing pulmonary disease by performing bone marrow transplantations using B6 and Abcg1−/− bone marrow. We found that it was the macrophage, and not pneumocyte type II cells or other nonhematopoietic cells in the lung, that appeared to be the primary cell type involved in the onset of both pulmonary lipidosis and inflammation in the Abcg1−/− mice. Additionally, our results demonstrate that Abcg1−/− macrophages had elevated proinflammatory cytokine production, increased apoptotic cell clearance, and were themselves more prone to apoptosis and necrosis. However, they were quickly repopulated by monocytes that were recruited to Abcg1−/− lungs. In conclusion, we have shown that ABCG1 deletion in macrophages causes a striking inflammatory phenotype and initiates onset of pulmonary lipidosis in mice. Thus, our studies reveal a critical role for macrophage ABCG1 in lung inflammation and homeostasis.

Differential expression and function of ABCG1 and ABCG4 during development and aging

“…mice to increased apoptosis ( 19,44,45 ). Our inability to measure changes in oxysterol levels in the retinas of Abcg1 ( Table 2 ) and 7-dehydrocholesterol, desmosterol, and testis meiosisactivating sterol (data not shown).…”

“…These changes in cholesterogenic genes is age dependent as the mRNA levels of 2 month old DKO and wild-type mice are not signifi cantly different ( Table 2 ). Indeed, these age-dependent changes in the brain are reminiscent of the age-dependent accumulation of cholesterol, phospholipids, and infl ammatory genes that have been shown to occur in the lungs of Abcg1 Ϫ / Ϫ mice ( 44,49 ). The fi nding that aberrant expression of genes involved in cholesterol synthesis and uptake is more pronounced in the brains compared with the retinas of DKO mice suggests that cholesterol homeostasis in the brain is more dependent than the retina upon these two ABC transporters.…”

Mechanisms of Neutrophil Accumulation in the Lungs Against Bacteria

“…Cholesterol overloading induces macrophages to produce cytokines, in part through endoplasmic reticulum stress (67)(68)(69), though it may also either enhance or attenuate macrophage responses to LPS (70,71). Hypercholesterolemia primes PMNs for oxidant and granule protein release (72,73), induces PMN adhesion to and emigration from postcapillary venules (74), and promotes mononuclear cell accumulation in vascular lesions by inducing endothelial chemokines (75,76).…”

“…For example, genetic deletion of the cellular cholesterol efflux pump ATP-binding cassette transporter G1 (ABCG1) induces recruitment of multiple leukocyte subtypes, including PMNs, to the unexposed murine lung (67,69), responses that reflect cooperative proinflammatory contributions from cholesterol-overloaded alveolar epithelium and alveolar macrophages. Conversely, the potential for therapies that reduce cellular and serum cholesterol to reduce PMN recruitment to the airspace has also been reported.…”

Impact of environmental factors on alloimmunity and transplant fate

“…Cholesterol also plays an important role in membrane maintenance that is critical for proper antigen-presenting cell (APC) function (65,66). Abcg1 -/-macrophages, which have impaired cholesterol efflux and elevated cholesterol levels, exhibited an intrinsic bias toward M1 polarization with increased NF-κB activation (67) and enhanced proinflammatory cytokine production (68,69). Oxidized LDL (ox-LDL) induced autophagosome formation, MHC-II expression, and phosphorylation of SYK in macrophages (70).…”