L-Plastin Is Essential for Alveolar Macrophage Production and Control of Pulmonary Pneumococcal Infection

Deady, Lauren E.; Todd, Elizabeth M.; Davis, Christopher G.; Zhou, Julie Y.; Topcagic, Nermina; Edelson, Brian T.; Ferkol, Thomas; Cooper, Megan A.; Muenzer, Jared T.; Morley, Sharon Celeste

doi:10.1128/iai.01199-13

Cited by 26 publications

(45 citation statements)

References 64 publications

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“…5,6,27 LPL 2/2 mice, in which all hematopoietic cells lack LPL, exhibited impaired pneumococcal clearance and increased susceptibility to infection. 23 To distinguish a cell-intrinsic requirement for LPL in alveolar macrophages from potential requirements in other immune cells (eg, neutrophils) during acute bacterial pneumonia, we assessed bacterial clearance and dissemination in CD11c. LPL is required during neonatal development as prealveolar macrophages transition to mature alveolar macrophages…”

Section: Cell-intrinsic Requirement For Lpl In Alveolar Macrophages Imentioning

confidence: 99%

“…23 Mice were euthanized 24 hours after challenge, and blood and BAL fluid were obtained for culture.…”

Section: Infectionmentioning

confidence: 99%

“…Lungs and spleens were homogenized using 2.5 mg/mL Collagenase D in Hanks balanced salt solution 1 3% fetal calf serum. 23,25 Alveolar macrophages were cultured in D10 (Dulbecco's modified Eagle medium supplemented with10% fetal calf serum). Cells deprived of serum prior to stimulation were incubated in serum-free D10 with 2% bovine serum albumin.…”

Section: Cell Isolation and Mediamentioning

confidence: 99%

“…Bronchoalveolar lavage (BAL) was performed as described, 23 and cells were quantified by flow cytometry. Lungs and spleens were homogenized using 2.5 mg/mL Collagenase D in Hanks balanced salt solution 1 3% fetal calf serum.…”

Section: Cell Isolation and Mediamentioning

confidence: 99%

“…[16][17][18][19][20] In macrophages, LPL colocalizes with actin-supported structures and is concentrated in podosomes, which are integrinanchored, actin-based complexes that support motility and adhesion. 21,22 Building on our prior observation of reduced alveolar macrophage numbers in LPL 2/2 mice, 23 we now use these and newly generated CD11c.Cre For personal use only. on June 7, 2019.…”

Section: Introductionmentioning

confidence: 99%

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Alveolar macrophage development in mice requires L-plastin for cellular localization in alveoli

Todd¹,

Zhou²,

Szasz³

et al. 2016

Blood

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Key Points• A key transition from the prealveolar macrophage precursor to mature alveolar macrophage is impaired in neonatal mice lacking LPL.• Genetic impairment of neonatal alveolar macrophage development associates with impaired clearance of a pulmonary pathogen in adult animals. ) exhibited significant reductions in alveolar macrophages and failed to effectively clear pulmonary pneumococcal infection, showing that immunodeficiency results from reduced alveolar macrophage numbers. We next identified the phase of alveolar macrophage development requiring LPL. In mice, fetal monocytes arrive in the lungs during a late fetal stage, maturing to alveolar macrophages through a prealveolar macrophage intermediate. LPL was required for the transition from prealveolar macrophages to mature alveolar macrophages. The transition from prealveolar macrophage to alveolar macrophage requires the upregulation of the transcription factor peroxisome proliferatoractivated receptor-g (PPAR-g), which is induced by exposure to granulocyte-macrophage colony-stimulating factor (GM-CSF). Despite abundant lung GM-CSF and intact GM-CSF receptor signaling, PPAR-g was not sufficiently upregulated in developing alveolar macrophages in LPL 2/2 pups, suggesting that precursor cells were not correctly localized to the alveoli, where GM-CSF is produced. We found that LPL supports 2 actin-based processes essential for correct localization of alveolar macrophage precursors: (1) transmigration into the alveoli, and (2) engraftment in the alveoli. We thus identify a molecular pathway governing neonatal alveolar macrophage development and show that genetic disruption of alveolar macrophage development results in immunodeficiency. (Blood. 2016;128(24):2785-2796

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Section: Cell-intrinsic Requirement For Lpl In Alveolar Macrophages Imentioning

confidence: 99%

“…23 Mice were euthanized 24 hours after challenge, and blood and BAL fluid were obtained for culture.…”

Section: Infectionmentioning

confidence: 99%

Section: Cell Isolation and Mediamentioning

confidence: 99%

Section: Cell Isolation and Mediamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Alveolar macrophage development in mice requires L-plastin for cellular localization in alveoli

Todd¹,

Zhou²,

Szasz³

et al. 2016

Blood

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Follow that cell: Leukocyte migration in L‐plastin mutant zebrafish

et al. 2022

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Actin assemblies are important in motile cells such as leukocytes, which form dynamic plasma membrane extensions or podia. L‐plastin (LCP1) is a leukocyte‐specific calcium‐dependent actin‐bundling protein that, in mammals, is known to affect immune cell migration. Previously, we generated CRISPR/Cas9 engineered zebrafish lacking L‐plastin (lcp1−/−) and reported that they had reduced survival to adulthood, suggesting that lack of this actin‐bundler might negatively affect the immune system. To test this hypothesis, we examined the distribution and migration of neutrophils and macrophages in the transparent tail of early zebrafish larvae using cell‐specific markers and an established wound‐migration assay. Knockout larvae were similar to their heterozygous siblings in having equal body sizes and comparable numbers of neutrophils in caudal hematopoietic tissue at 2 days postfertilization, indicating no gross defect in neutrophil production or developmental migration. When stimulated by a tail wound, all genotypes of neutrophils were equally migratory in a two‐hour window. However, for macrophages we observed both migration defects and morphological differences. L‐plastin knockout macrophages (lcp1 −/−) still homed to wounds but were slower, less directional and had a star‐like morphology with many leading and trailing projections. In contrast, heterozygous macrophages lcp1 (+/−) were faster, more directional, and had a streamlined, slug‐like morphology. Overall, these findings show that in larval zebrafish L‐plastin knockout primarily affects the macrophage response with possible consequences for organismal immunity. Consistent with our observations, we propose a model in which cytoplasmic L‐plastin negatively regulates macrophage integrin adhesion by holding these transmembrane heterodimers in a “clasped,” inactive form and is a necessary part of establishing macrophage polarity during chemokine‐induced motility.

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The actin-bundling protein L-plastin—A double-edged sword: Beneficial for the immune response, maleficent in cancer

Schaffner-Reckinger

Machado

2020

International Review of Cell and Molecular Biology

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L-Plastin Is Essential for Alveolar Macrophage Production and Control of Pulmonary Pneumococcal Infection

Cited by 26 publications

References 64 publications

Alveolar macrophage development in mice requires L-plastin for cellular localization in alveoli

Alveolar macrophage development in mice requires L-plastin for cellular localization in alveoli

Follow that cell: Leukocyte migration in L‐plastin mutant zebrafish

The actin-bundling protein L-plastin—A double-edged sword: Beneficial for the immune response, maleficent in cancer

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