Structural Basis for Interactions between Lung Surfactant Protein C and Bacterial Lipopolysaccharide

Augusto, Luis; Li, Jing; Synguélakis, Monique; Johansson, Jan; Chaby, Richard

doi:10.1074/jbc.m111925200

Cited by 59 publications

(60 citation statements)

References 44 publications

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“…This finding is consistent with previous studies showing SP-C binding with Salmonella LPS (14,32). These data suggest that SP-C likely associates with a range of gram-; Figure 6.…”

Section: Discussionsupporting

confidence: 93%

Persistence of LPS-Induced Lung Inflammation in Surfactant Protein-C–Deficient Mice

Glasser

Maxfield²,

Ruetschilling³

et al. 2013

Am J Respir Cell Mol Biol

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Pulmonary surfactant protein-C (SP-C) gene-targeted mice (Sftpc 2/2 ) develop progressive lung inflammation and remodeling. We hypothesized that SP-C deficiency reduces the ability to suppress repetitive inflammatory injury. Sftpc 1/1 and Sftpc 2/2 mice given three doses of bacterial LPS developed airway and airspace inflammation, which was more intense in the Sftpc 2/2 mice at 3 and 5 days after the final dose. Compared with Sftpc 1/1 mice, inflammatory injury persisted in the lungs of Sftpc 2/2 mice 30 days after the final LPS challenge. Sftpc 2/2 mice showed LPS-induced airway goblet cell hyperplasia with increased detection of Sam pointed Ets domain and FoxA3 transcription factors. Sftpc 2/2 type II alveolar epithelial cells had increased cytokine expression after LPS exposure relative to Sftpc 1/1 cells, indicating that type II cell dysfunction contributes to inflammatory sensitivity. Microarray analyses of isolated type II cells identified a pattern of enhanced expression of inflammatory genes consistent with an intrinsic low-level inflammation resulting from SP-C deficiency. SP-C-containing clinical surfactant extract (Survanta) or SP-C/phospholipid vesicles blocked LPS signaling through the LPS receptor (Toll-like receptor [TLR] 4/CD14/MD2) in human embryonic kidney 293T cells, indicating that SP-C blocks LPS-induced cytokine production by a TLR4-dependent mechanism. Phospholipid vesicles alone did not modify the TLR4 response. In vivo deficiency of SP-C leads to inflammation, increased cytokine production by type II cells, and persistent inflammation after repetitive LPS stimulation.Keywords: surfactant protein-C; LPS; lung inflammation; type II cells; Toll-like receptor 4Surfactant protein-C (SP-C) is an abundant 3.5-kD surfactantassociated protein expressed and secreted by alveolar type II epithelial cells. The mature airspace form of SP-C is highly hydrophobic and palmitoylated at adjacent amino terminal cysteine residues (1). Mutations in the gene encoding human SP-C (SFTPC) have been shown to cause familial interstitial lung disease (ILD). Affected individuals express an altered proSP-C, leading to reduced levels of mature SP-C in the airspace (2-4). SP-C deficiencies without detectable mutations in the protein-coding region of SFTPC or due to promoter mutations have also been reported, and represent a true null condition (5-7). These individuals also develop ILD, including idiopathic pulmonary fibrosis (IPF). SP-C deficiency-related disease may arise as an acute childhood or as a late-onset disease in adulthood (3). Because SP-C is expressed exclusively in alveolar type II cells, the associated ILD/idiopathic pulmonary fibrosis presumably originates from a primary defect in the epithelium. SP-C deficiency increases susceptibility to viral-or bacterial-induced exacerbations in affected children (5,6,(8)(9)(10). SP-C-deficient mice (Sftpc 2/2 ) developed a strain-specific pulmonary phenotype with age that was similar to the human disease (11). Sftpc 2/2 mice were more susceptible to challenge with ...

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“…This finding is consistent with previous studies showing SP-C binding with Salmonella LPS (14,32). These data suggest that SP-C likely associates with a range of gram-; Figure 6.…”

Section: Discussionsupporting

confidence: 93%

Persistence of LPS-Induced Lung Inflammation in Surfactant Protein-C–Deficient Mice

Glasser

Maxfield²,

Ruetschilling³

et al. 2013

Am J Respir Cell Mol Biol

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“…Of the different bacterial components, LPS is one of the most active in the host. Recent work in this laboratory (3,4) has demonstrated a new feature of the surfactant component SP-C, its ability to interact with LPS. This opens new perspectives for a possible role of SP-C in innate immunity, since by binding to LPS, SP-C may affect the interaction of this molecule with cellular receptors and thus influence the cell signaling reactions and the ensuing pathophysiological cascade.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its surface tension-lowering activity, pulmonary surfactant also displays host defense capacities (32). SP-A and SP-D have been shown to interact with LPSs of various phenotypes (20,25), and we have shown recently that SP-C, but not SP-B, can also do so (3,4).…”

mentioning

confidence: 96%

Interaction of Pulmonary Surfactant Protein C with CD14 and Lipopolysaccharide

et al. 2003

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In addition to their effects on alveolar surface tension, some components of lung surfactant also have immunological functions. We found recently that the hydrophobic lung surfactant protein SP-C specifically binds to the lipid A region of lipopolysaccharide (LPS). In this study, we show that SP-C also interacts with CD14. Four observations showed cross talk between the three molecules SP-C, LPS, and CD14.

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“…This extract is reported to lack only the hydrophilic SP-A. Therefore, assuming that the hydrophobic surfactant proteins SP-B and SP-C are effectively present in Survanta, our data indicate that these proteins do not affect Y. pestis, despite their antibacterial and/or LPS-binding properties (4,51). To characterize the antimicrobial molecules present in rBALF, the soluble fraction was subjected to gel filtration chromatography.…”

mentioning

confidence: 84%

Capsular Antigen Fraction 1 and Pla Modulate the Susceptibility of Yersinia pestis to Pulmonary Antimicrobial Peptides Such as Cathelicidin

2008

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Inhaled Yersinia pestis produces a severe primary pneumonia known as pneumonic plague, which is contagious and highly lethal to humans and animals. In this study, we first determined the susceptibility of Y. pestis KIM6 to antimicrobial molecules of the airways. We found that (i) rat bronchoalveolar lavage fluid (rBALF) effectively killed KIM6 cells growing at 37°C; (ii) the antibacterial components of rBALF were small peptides (<10 kDa) that included two cationic antimicrobial peptides (CAMPs), the rat cathelicidin rCRAMP, and ␤-defensin RBD-1; (iii) the human cathelicidin LL-37 killed KIM6 cells as well as rBALF did; and (iv) the bactericidal property of LL-37 was synergistically amplified by human ␤-defensin 1, another constitutively expressed pulmonary CAMP. Second, the effects of three major surface proteins of Y. pestis, namely, the capsular antigen fraction 1 (F1), the pH 6 antigen (Psa fimbriae), and the outer membrane protease Pla, on the bactericidal effect of the antimicrobial rBALF peptides was determined with corresponding deletion mutants. We showed that (i) a Y. pestis psa mutant was only slightly more susceptible to rBALF than the parental KIM6 strain, (ii) a caf (F1 gene) mutant and a caf psa mutant were resistant to rBALF or LL-37, (iii) a caf pla mutant was as susceptible to the effect of rBALF or LL-37 as KIM6 was (caf ؉ pla ؉ ), and (iv) only the single caf mutant (pla ؉ ), but not KIM6 or the caf pla double mutant, degraded LL-37. The activity of Pla toward LL-37 was confirmed with pla mutants carrying a single-residue substitution affecting plasminogen cleavage. Taken together, our data indicated that Pla might act as a virulence factor not only by processing plasminogen but also by inactivating CAMPs, particularly when F1 is not expressed.

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Structural Basis for Interactions between Lung Surfactant Protein C and Bacterial Lipopolysaccharide

Cited by 59 publications

References 44 publications

Persistence of LPS-Induced Lung Inflammation in Surfactant Protein-C–Deficient Mice

Persistence of LPS-Induced Lung Inflammation in Surfactant Protein-C–Deficient Mice

Interaction of Pulmonary Surfactant Protein C with CD14 and Lipopolysaccharide

Capsular Antigen Fraction 1 and Pla Modulate the Susceptibility of Yersinia pestis to Pulmonary Antimicrobial Peptides Such as Cathelicidin

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