Targeted PPARγ deficiency in alveolar macrophages disrupts surfactant catabolism

Baker, Anna D.; Barna, Barbara P.; Ghosh, Shobha; Kavuru, Mani S.; Malur, Anagha; Thomassen, Mary Jane

doi:10.1194/jlr.m001651

Cited by 98 publications

(86 citation statements)

References 53 publications

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“…Extraction of sets of M1 and M2 macrophage genes from the microarray analysis revealed the upregulation of more M1 genes than M2 genes in T-bet tg/tg mice, indicating aberrant activation of both the M1 and M2 programs ( Figure 2F). Expression analysis of the genes previously related to lipid handling in macrophages and PAP development [29][30][31][32][33] showed a marked reduction of Pparg and Abcg1 mRNA expression levels, but upregulation of Abca1 and Bach2 mRNA expression levels in AF 1 populations from mice with PAP phenotype ( Figure 2G). In addition, phagocytic assay using fluorescein isothiocyanate-labeled beads demonstrated a reduction of the bead uptake by T-bet tg/tg BAL cells compared with WT (supplemental Figure 5C).…”

Section: Subpopulations Of Bal Cells Are Altered In the Lungs Of Papmentioning

confidence: 97%

T-cell–restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung

Iriguchi

Kikuchi

Kaneko

et al. 2015

Blood

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Key Points• Mice overexpressing T-bet in T cells show aberrant hematopoiesis of myeloid cells and functional conversion of regional macrophages.• The mice developed a severe PAP-like disease with a hematopoietic disorder resembling the human disease.Although overexpression of T-bet, a master transcription factor in type-1 helper T lymphocytes, has been reported in several hematologic and immune diseases, its role in their pathogenesis is not fully understood. In the present study, we used transgenic model mice (T-bet tg/wt and T-bet tg/tg ) to investigate the effects of T-bet overexpression selectively in T lymphocytes on the development of hematologic and immune diseases. The results showed that T-bet overexpression in T cells spontaneously induced maturation arrest in the mononuclear phagocyte lineage, as well as spontaneous dermatitis and pulmonary alveolar proteinosis (PAP)-like disease in T-bet tg/wt and T-bet tg/tg mice, respectively. T-bet tg/tg alveoli with the PAP phenotype showed remarkable reorganization of alveolar mononuclear phagocyte subpopulations and impaired function, in addition to augmented T-cell infiltration. In addition, PAP development in T-bet tg/tg mice was found to be associated with increased migration of myeloid cells from the bone marrow into the peripheral blood. These findings reveal an unexpected link between T-bet overexpression in T lymphocytes and the development of PAP caused by reorganization of mononuclear phagocytes in the lung, and provide new insight into the molecular pathogenesis of secondary PAP accompanied by hematologic disorders. (Blood. 2015;125(2):370-382)

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Section: Subpopulations Of Bal Cells Are Altered In the Lungs Of Papmentioning

confidence: 97%

T-cell–restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung

Iriguchi

Kikuchi

Kaneko

et al. 2015

Blood

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“…The AM accretion of lipid is attributed to compromised catabolic capacity (10) and affected signalling cascade(s) downstream of GM-CSF involving PPARγ have been extensively characterised (14,15). cells increases alveolar surfactant but leads to a neutral lipid accumulation in AT2 cells (17).…”

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confidence: 99%

Hepatic Steatosis Accompanies Pulmonary Alveolar Proteinosis

Hunt

Malur

Monfort

et al. 2017

Am J Respir Cell Mol Biol

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Maintenance of tissue-specific organ lipid compositions characterises mammalian lipid homeostasis. Lung and liver synthesise mixed phosphatidylcholine (PC) molecular species subsequently "tailored" for function. Lungs progressively enrich disaturated PC (DSPC) directed to lamellar body (LB) surfactant stores prior to secretion. Liver accumulates polyunsaturated PC directed to VLDL assembly and secretion, or triglyceride stores. In each tissue, selective PC species enrichment mechanisms lie at the heart of effective homeostasis. We tested potential coordination between these spatially separated, but possibly complementary phenomena under a major derangement of lung PC metabolism, Pulmonary Alveolar Proteinosis (PAP), which overwhelms homeostasis leading to excessive surfactant accumulation. Using static and dynamic lipidomics techniques we compared (i) tissue PC compositions and contents and (ii) in lungs, the absolute rates of synthesis from both control mice and the GM-CSF knockout model of PAP. Significant DSPC accumulation in BALF, Alveolar Macrophage (AM) and lavaged lung tissue occurred alongside increased PC synthesis consistent with reported defects in AM surfactant turnover. However, microscopy using oil red O staining, CARS, SHG and TEM also revealed neutral lipid droplet accumulations in alveolar lipofibroblasts of GM-CSF KO animals suggesting lipid homeostasis deficits extend beyond AMs. PAP plasma PC composition was significantly PUFA-enriched but content was unchanged and hepatic PUFA-enriched PC content increased by 50% with an accompanying micro/macrovesicular steatosis and a fibrotic damage pattern consistent with NAFLD. These data suggest a hepato-pulmonary axis of PC metabolism coordination with wider implications for understanding and managing lipid pathologies where compromise of one organ has unexpected consequences for another.

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“…Although cholesterol is a minor component of surfactant compared with phospholipid (37), our findings indicate that modification of cholesterol metabolism has a profound effect on restoration of surfactant homeostasis. Several lines of evidence suggest that PPAR␥ may regulate intracellular lipid accumulation and cholesterol efflux indirectly via upregulation of a key lipid transporter, ABCG1: 1) Our previous data indicate that lungs of untreated macrophage-specific PPAR␥ KO mice exhibit ABCG1 deficiency together with accumulation of both surfactant and cholesterol (5). 2) Data from the current paper indicate that administration of lenti-PPAR␥ to GM-CSF KO mice increases levels of ABCG1 and cholesterol efflux.…”

Section: Discussionmentioning

confidence: 77%

“…Although weakly expressed in monocytes, PPAR␥ expression increases with macrophage differentiation and is predominantly nuclear in location (15). A critical role for PPAR␥ has also been reported in regulation of genes involved in lipid and glucose metabolism as well as in inflammation (5,8,24).…”

mentioning

confidence: 99%

“…Furthermore, PAP patients receiving GM-CSF therapy demonstrated in vivo PPAR␥ and ACBG1 upregulation in their alveolar macrophages (11,34). Our recent studies in macrophage-specific PPAR␥ KO mice that are not deficient in GM-CSF or PU.1 also detected decreased ABCG1 gene and protein expression as well as cholesterol accumulation in alveolar macrophages (4,5). However, the effect of PPAR␥ replacement has not been investigated in the GM-CSF KO mouse, which is recognized as a murine model of human PAP.…”

mentioning

confidence: 99%

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Restoration of PPARγ reverses lipid accumulation in alveolar macrophages of GM-CSF knockout mice

Malur¹,

Baker²,

McCoy³

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Pulmonary alveolar proteinosis (PAP) is a lung disease characterized by a deficiency of functional granulocyte macrophage colony-stimulating factor (GM-CSF) resulting in surfactant accumulation and lipidengorged alveolar macrophages. GM-CSF is a positive regulator of PPAR␥ that is constitutively expressed in healthy alveolar macrophages. We previously reported decreased PPAR␥ and ATP-binding cassette transporter G1 (ABCG1) levels in alveolar macrophages from PAP patients and GM-CSF knockout (KO) mice, suggesting PPAR␥ and ABCG1 involvement in surfactant catabolism. Because ABCG1 represents a PPAR␥ target, we hypothesized that PPAR␥ restoration would increase ABCG1 and reduce macrophage lipid accumulation. Upregulation of PPAR␥ was achieved using a lentivirus expression system in vivo. GM-CSF KO mice received intratracheal instillation of lentivirus (lenti)-PPAR␥ or control lenti-eGFP. Ten days postinstillation, 79% of harvested alveolar macrophages expressed eGFP, demonstrating transduction. Alveolar macrophages showed increased PPAR␥ and ABCG1 expression after lenti-PPAR␥ instillation, whereas PPAR␥ and ABCG1 levels remained unchanged in lentieGFP controls. Alveolar macrophages from lenti-PPAR␥-treated mice also exhibited reduced intracellular phospholipids and increased cholesterol efflux to HDL, an ABCG1-mediated pathway. In vivo instillation of lenti-PPAR␥ results in: 1) upregulating ABCG1 and PPAR␥ expression of GM-CSF KO alveolar macrophages, 2) reducing intracellular lipid accumulation, and 3) increasing cholesterol efflux activity.

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Targeted PPARγ deficiency in alveolar macrophages disrupts surfactant catabolism

Cited by 98 publications

References 53 publications

T-cell–restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung

T-cell–restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung

Hepatic Steatosis Accompanies Pulmonary Alveolar Proteinosis

Restoration of PPARγ reverses lipid accumulation in alveolar macrophages of GM-CSF knockout mice

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