Hyaluronan and Its Interactions With Immune Cells in the Healthy and Inflamed Lung

Johnson, Pauline; Arif, Arif A.; Lee-Sayer, Sally S. M.; Dong, Yifei

doi:10.3389/fimmu.2018.02787

Cited by 76 publications

(71 citation statements)

References 105 publications

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“…Apart from the tissue resident AMs, there were significantly greater numbers of other leukocytes (neutrophils, monocytes, eosinophils) in the BAL from CD44 −/− mice (Figure 5C). Protein and HA levels, both indicators of lung inflammation and damage (23,28,29), were also increased after POVPC treatment and were higher in the BAL from CD44 −/− mice ( Figures 5D,E). There was also increased HA detected by HABP labeling in the lung tissue of CD44 −/− mice 3 days after POVPC treatment, a sign of increased lung inflammation (Figures 5F,G).…”

Section: Cd44 −/− Ams Have More Lipid Droplets Increased Ros and Higmentioning

confidence: 90%

“…Unlike most other macrophages at steady state, mature murine AMs express high levels of CD11c, Siglec F, and constitutively bind hyaluronan (HA) via its receptor, CD44 (21,22). HA, a component of the extracellular matrix, is implicated in both lung homeostasis and inflammation (23). At homeostasis, CD44-dependent HA binding by AMs results in the formation of a pericellular HA coat that promotes their survival (12).…”

Section: Introductionmentioning

confidence: 99%

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CD44 Loss Disrupts Lung Lipid Surfactant Homeostasis and Exacerbates Oxidized Lipid-Induced Lung Inflammation

et al. 2020

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Alveolar macrophages (AMs) are CD44 expressing cells that reside in the alveolar space where they maintain lung homeostasis by serving critical roles in immunosurveillance and lipid surfactant catabolism. AMs lacking CD44 are unable to bind the glycosaminoglycan, hyaluronan, which compromises their survival and leads to reduced numbers of AMs in the lung. Using RNA sequencing, lipidomics and multiparameter flow cytometry, we demonstrate that CD44 −/− mice have impaired AM lipid homeostasis and increased surfactant lipids in the lung. CD44 −/− AMs had increased expression of CD36, a lipid scavenger receptor, as well as increased intracellular lipid droplets, giving them a foamy appearance. RNA sequencing revealed the differential expression of genes associated with lipid efflux and metabolism in CD44 −/− AMs. Lipidomic analysis showed increased lipids in both the supernatant and cell pellet extracted from the bronchoalveolar lavage of CD44 −/− mice. Phosphatidylcholine species, cholesterol, oxidized phospholipids and levels of reactive oxygen species (ROS) were increased in CD44 −/− AMs. Oxidized phospholipids were more cytotoxic to CD44 −/− AMs and induced greater lung inflammation in CD44 −/− mice. Reconstitution of CD44 +/+ mice with CD44 −/− bone marrow as well as adoptive transfer of CD44 −/− AMs into CD44 +/+ mice showed that lipid accumulation in CD44 −/− AMs occurred irrespective of the lung environment, suggesting a cell intrinsic defect. Administration of colony stimulating factor 2 (CSF-2), a critical factor in AM development and maintenance, increased AM numbers in CD44 −/− mice and decreased phosphatidylcholine levels in the bronchoalveolar lavage, but was unable to decrease intracellular lipid accumulation in CD44 −/− AMs. Peroxisome proliferator-activated receptor gamma (PPARγ), downstream of CSF-2 signaling and a regulator of lipid metabolism, was reduced in the nucleus of CD44 −/− AMs, and PPARγ inhibition in normal AMs increased their lipid droplets. Thus, CD44 deficiency causes defects in AMs that lead to abnormal lipid accumulation and oxidation, which exacerbates oxidized lipid-induced lung inflammation. Collectively, these findings implicate CD44 as a regulator of lung homeostasis and inflammation.

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Section: Cd44 −/− Ams Have More Lipid Droplets Increased Ros and Higmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

CD44 Loss Disrupts Lung Lipid Surfactant Homeostasis and Exacerbates Oxidized Lipid-Induced Lung Inflammation

et al. 2020

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“…At present it also remains unclear whether ECM-CD44 engagement drives stemness phenotypes, or whether the engagement of already upregulated CD44 ligands with ECM components such as hyaluronan preferentially supports cancer cells with stem-like phenotypes. In the normal lung, hyaluronan is expressed by multiple cell types in response to injury, where it is involved in the fibrosis and wound repair response and modulates lung inflammation (114). However, in lung cancer, hyaluronan has been shown to promote the outgrowth of NSCLC tumors (39).…”

Section: Hyaluronanmentioning

confidence: 99%

The Role of the ECM in Lung Cancer Dormancy and Outgrowth

Parker

Cox

2020

Front. Oncol.

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“…Apart from the tissue resident AMs, there were significantly greater numbers of other leukocytes (neutrophils, monocytes, eosinophils) in the BAL from CD44 -/mice ( Figure 5C). Protein and HA levels, both indicators of lung inflammation and damage (23,28,29), were also increased after POVPC treatment and were higher in the BAL from CD44 -/mice ( Figure 5D-E). There was also increased HA detected by HABP labeling in the lung tissue of CD44 -/mice 3 days after POVPC treatment, a sign of increased lung inflammation ( Figure F-G).…”

Section: The Inflammatory Response To Oxpc Is Exacerbated In Cd44 -/Micementioning

confidence: 90%

RNA sequencing and lipidomic analysis of alveolar macrophages from normal and CD44 deficient mice

Dong

Arif

Guo

et al. 2019

Preprint

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ABSTRACTAlveolar macrophages (AMs) are CD44 expressing cells that reside in the alveolar space where they maintain lung homeostasis by serving critical roles in immunosurveillance and lipid surfactant catabolism. AMs lacking CD44 are unable to bind the glycosaminoglycan, hyaluronan, which compromises their survival and leads to reduced numbers of AMs in the lung. Using RNA sequencing, lipidomics and multiparameter flow cytometry, we demonstrate that CD44-/- mice have impaired AM lipid homeostasis and increased surfactant lipids in the lung. CD44-/- AMs had increased expression of CD36, a lipid scavenger receptor, as well as increased intracellular lipid droplets, giving them a foamy appearance. RNA sequencing revealed the differential expression of genes associated with lipid efflux and metabolism in CD44-/- AMs. Lipidomic analysis showed increased lipids in both the supernatant and cell pellet extracted from the bronchoalveolar lavage of CD44-/- mice. Phosphatidylcholine species, cholesterol, oxidized phospholipids and levels of reactive oxygen species (ROS) were increased in CD44-/- AMs. Oxidized phospholipids were more cytotoxic to CD44-/- AMs and induced greater lung inflammation in CD44-/- mice. Reconstitution of CD44+/+ mice with CD44-/- bone marrow as well as adoptive transfer of CD44-/- AMs into CD44+/+ mice showed that lipid accumulation in CD44-/- AMs occurred irrespective of the lung environment, suggesting a cell intrinsic defect. Administration of colony stimulating factor 2 (CSF-2), a critical factor in AM development and maintenance, increased AM numbers in CD44-/- mice and decreased phosphatidylcholine levels in the bronchoalveolar lavage, but was unable to decrease intracellular lipid accumulation in CD44-/- AMs. Peroxisome proliferator-activated receptor gamma (PPARγ), downstream of CSF-2 signaling and a regulator of lipid metabolism, was reduced in the nucleus of CD44-/- AMs, and PPARγ inhibition in normal AMs increased their lipid droplets. Thus, CD44 deficiency causes defects in AMs that lead to abnormal lipid accumulation and oxidation, which exacerbates oxidized lipid-induced lung inflammation. Collectively, these findings implicate CD44 as a regulator of lung homeostasis and inflammation.

show abstract

Hyaluronan and Its Interactions With Immune Cells in the Healthy and Inflamed Lung

Cited by 76 publications

References 105 publications

CD44 Loss Disrupts Lung Lipid Surfactant Homeostasis and Exacerbates Oxidized Lipid-Induced Lung Inflammation

CD44 Loss Disrupts Lung Lipid Surfactant Homeostasis and Exacerbates Oxidized Lipid-Induced Lung Inflammation

The Role of the ECM in Lung Cancer Dormancy and Outgrowth

RNA sequencing and lipidomic analysis of alveolar macrophages from normal and CD44 deficient mice

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