The Actin-Bundling Protein L-Plastin Is Essential for Marginal Zone B Cell Development

Todd, Elizabeth M.; Deady, Lauren E.; Morley, Sharon Celeste

doi:10.4049/jimmunol.1101033

Cited by 42 publications

(59 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Concurrent with this hypothesis, we observed a significant decrease in the lysosomal enzyme hexosaminidase B that plays a role in degradation of internalized Staphylococcus (106). Taken together, the regulatory systems described generate precise control of actin filament and network formation and participate in multiple aspects of pathogenesis (107)(108)(109)(110)(111)(112).…”

Section: Discussionsupporting

confidence: 48%

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

Harrison

Dubois

John-Williams

et al. 2016

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

A thorough understanding of the molecular details of the interactions between bacteria and host are critical to ultimately prevent disease. Recent technological advances allow simultaneous analysis of host and bacterial protein and metabolic profiles from a single small tissue sample to provide insight into pathogenesis. We used the chinchilla model of human otitis media to determine, for the first time, the most expansive delineation of global changes in protein and metabolite profiles during an experimentally induced disease. After 48 h of infection with nontypeable Haemophilus influenzae, middle ear tissue lysates were analyzed by high-resolution quantitative two-dimensional liquid chromatography-tandem mass spectrometry. Dynamic changes in 105 chinchilla proteins and 66 metabolites define the early proteomic and metabolomic signature of otitis media. Our studies indicate that establishment of disease coincides with actin morphogenesis, suppression of inflammatory mediators, and bacterial aerobic respiration. We validated the observed increase in the actin-remodeling complex, Arp2/3, and experimentally showed a role for Arp2/3 in nontypeable Haemophilus influenzae invasion. Direct inhibition of actin branch morphology altered bacterial invasion into host epithelial cells, and is supportive of our efforts to use the information gathered to modify outcomes of disease. The twenty-eight nontypeable Haemophilus influenzae proteins identified participate in carbohydrate and amino acid metabolism, redox homeostasis, and include cell wall-associated metabolic proteins. Quantitative characterization of the molecular signatures of infection will redefine our understanding of host response driven developmental changes during pathogenesis. These data represent the first comprehensive study of host protein and metabolite profiles in vivo in response to infection and show the feasibility of extensive characterization of host protein profiles during disease. Identification of novel protein targets and metabolic biomarkers will advance development of therapeutic and diagnostic options for treatment of disease. Molecular & Cellular Proteomics 15: 10.1074/mcp.M115.052498, 1117-1138, 2016.Our current understanding of the global changes that occur during infection is primarily based upon transcriptional profiles of either the host or the bacteria. However, a significant component of disease progression is dependent upon posttranscriptional processes. Recent advances in the application of two-dimensional tandem mass spectrometry have dramatically increased sensitivity to allow simultaneous analyses of multiple molecules from very small biological samples. In this study, we report the comprehensive proteomic and metabolomic profiling of middle ear tissues using samples that are smaller than those typically obtained from a human biopsy. Proteomic and metabolomic analyses of samples as small as biopsies will revolutionize the elucidation of the mechanisms From the

show abstract

Section: Discussionsupporting

confidence: 48%

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

Harrison

Dubois

John-Williams

et al. 2016

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

show abstract

“…First, monocyte precursors relied on LPL for normal migration into alveoli. Although LPL was previously shown to be required for normal motility in lymphocytes, 17,18,47 it was dispensable for motility in neutrophils. 15 The defect in monocyte alveolar transmigration in LPL 2/2 mice was more profound than that of monocyte trafficking into the peritoneum, 46 suggesting that different tissues present distinct environments for cellular migration.…”

Section: Discussionmentioning

confidence: 99%

“…18 Membranes were probed with either anti-LPL (provided by Eric J. Brown, Genentech) or with anti-PPAR-g (clone C26H12; Cell Signaling Technology, Danvers, MA).…”

Section: Immunoblotmentioning

confidence: 99%

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

Todd¹,

Zhou²,

Szasz³

et al. 2016

Blood

Self Cite

View full text Add to dashboard Cite

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

show abstract

“…LPL colocalizes with polymerized actin in macrophage podosomes, membrane ruffles, and phagocytic cups (10,11). The critical roles of LPL in neutrophil integrin signaling, T and B lymphocyte motility, and T cell activation have been established (12)(13)(14)(15)(16)(17)(18)(19), but a requirement for LPL in macrophage function has not. Here we show that LPL Ϫ/Ϫ mice challenged intratracheally (i.t.)…”

mentioning

confidence: 99%

“…Proliferation and cell death assays. Proliferation of alveolar macrophages was determined by measuring bromodeoxyuridine (BrdU) incorporation (17). BrdU incorporation was assessed (BrdU-APC kit; BD Biosciences) 24 h after mice were injected intraperitoneally (i.p.)…”

mentioning

confidence: 99%

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

et al. 2014

Self Cite

View full text Add to dashboard Cite

We report that mice deficient for the hematopoietic-specific, actin-bundling protein L-plastin (LPL) succumb rapidly to intratracheal pneumococcal infection. The increased susceptibility of LPL ؊/؊ mice to pulmonary pneumococcal challenge correlated with reduced numbers of alveolar macrophages, consistent with a critical role for this cell type in the immediate response to pneumococcal infection. LPL ؊/؊ mice demonstrated a very early clearance defect, with an almost 10-fold-higher bacterial burden in the bronchoalveolar lavage fluid 3 h following infection. Clearance of pneumococci from the alveolar space in LPL ؊/؊ mice was defective compared to that in Rag1 ؊/؊ mice, which lack all B and T lymphocytes, indicating that innate immunity is defective in LPL ؊/؊ mice. We did not identify defects in neutrophil or monocyte recruitment or in the production of inflammatory cytokines or chemokines that would explain the early clearance defect. However, efficient alveolar macrophage regeneration following irradiation required LPL. We thus identify LPL as being key to alveolar macrophage development and essential to an effective antipneumococcal response. Further analysis of LPL ؊/؊ mice will illuminate critical regulators of the generation of alveolar macrophages and, thus, effective pulmonary innate immunity.

show abstract

The Actin-Bundling Protein L-Plastin Is Essential for Marginal Zone B Cell Development

Cited by 42 publications

References 51 publications

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

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

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

Contact Info

Product

Resources

About