Surfactant Protein-A Inhibits <i>Mycoplasma</i>-Induced Dendritic Cell Maturation through Regulation of HMGB-1 Cytokine Activity

Ledford, Julie G.; Lo, Bernice; Kislan, Michèle M.; Thomas, J. M.; Evans, K; Cain, Derek W.; Kraft, Monica; Williams, Kristi; Wright, Jo Rae

doi:10.4049/jimmunol.1000387

Cited by 20 publications

(15 citation statements)

References 34 publications

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“…In previous studies using WT and SP-A −/− mice, we have shown that SP-A is protective against live Mp infection (23). Since SP-A binds Mp and acts as an opsonin, we sought to determine if the phenotypes observed in Mp-infected SP-A −/− mice were due to the increased pathogen burden, or innate recognition of pathogen-derived material.…”

Section: Introductionmentioning

confidence: 88%

Genetic Variation in SP-A2 Leads to Differential Binding to Mycoplasma pneumoniae Membranes and Regulation of Host Responses

Ledford

Voelker

Addison

et al. 2015

The Journal of Immunology

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Mycoplasma pneumoniae (Mp) is an extracellular pathogen that colonizes mucosal surfaces of the respiratory tract and is associated with asthma exacerbations. Previous reports demonstrate that surfactant protein-A (SP-A) binds live Mp and mycoplasma membranes (MMF) with high affinity. Humans express a repertoire of single amino acid genetic variants of SP-A that may be associated with lung disease, and our findings demonstrate that allelic differences in SP-A2 (Gln223Lys) affect the binding to MMF. We show that SP-A−/− mice are more susceptible to MMF exposure and have significant increases in mucin production and neutrophil recruitment. Novel humanized-SP-A2 transgenic mice harboring the hSP-A2 223K allele exhibit reduced neutrophil influx and mucin production in the lungs, when challenged with MMF, compared to SP-A−/− mice. Conversely, mice expressing hSP-A2 223Q have increased neutrophil influx and mucin production that is similar to SP-A−/− mice. Using tracheal epithelial cell cultures, we show that enhanced mucin production to MMF occurs in the absence of SP-A, and is not dependent upon neutrophil recruitment. Increased phosphorylation of the epidermal growth factor receptor (EGFR) was evident in the lungs of MMF-challenged mice when SP-A was absent. Pharmacologic inhibition of EGFR prior to MMF challenge dramatically reduced mucin production in SP-A−/− mice. These findings suggest a protective role for SP-A in limiting MMF-stimulated mucin production that occurs through interference with EGFR mediated signaling. The SP-A interaction with the EGFR signaling pathway appears to occur in an allele specific manner that may have important implications for SP-A polymorphisms in human diseases.

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Section: Introductionmentioning

confidence: 88%

Genetic Variation in SP-A2 Leads to Differential Binding to Mycoplasma pneumoniae Membranes and Regulation of Host Responses

Ledford

Voelker

Addison

et al. 2015

The Journal of Immunology

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“…Surfactant proteins, SP-A and SP-D, are found in serous cells (334,568) and kill bacteria by permeabilizing their membranes (750). SP-A is also an immune modulator (373).…”

Section: Proteins Peptides and Small Organic Moleculesmentioning

confidence: 99%

Airway Gland Structure and Function

Widdicombe

Wine

2015

Physiological Reviews

180

221

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Submucosal glands contribute to airway surface liquid (ASL), a film that protects all airway surfaces. Glandular mucus comprises electrolytes, water, the gel-forming mucin MUC5B, and hundreds of different proteins with diverse protective functions. Gland volume per unit area of mucosal surface correlates positively with impaction rate of inhaled particles. In human main bronchi, the volume of the glands is ∼ 50 times that of surface goblet cells, but the glands diminish in size and frequency distally. ASL and its trapped particles are removed from the airways by mucociliary transport. Airway glands have a tubuloacinar structure, with a single terminal duct, a nonciliated collecting duct, then branching secretory tubules lined with mucous cells and ending in serous acini. They allow for a massive increase in numbers of mucus-producing cells without replacing surface ciliated cells. Active secretion of Cl(-) and HCO3 (-) by serous cells produces most of the fluid of gland secretions. Glands are densely innervated by tonically active, mutually excitatory airway intrinsic neurons. Most gland mucus is secreted constitutively in vivo, with large, transient increases produced by emergency reflex drive from the vagus. Elevations of [cAMP]i and [Ca(2+)]i coordinate electrolyte and macromolecular secretion and probably occur together for baseline activity in vivo, with cholinergic elevation of [Ca(2+)]i being mainly responsive for transient increases in secretion. Altered submucosal gland function contributes to the pathology of all obstructive diseases, but is an early stage of pathogenesis only in cystic fibrosis.

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“…All three have been shown to be protective in models of acute inflammation . Both monoclonal and polyclonal antibodies that directly bind to HMGB1 as well as the small molecule glycyrrhizin, which binds to HMGB1 with high affinity, were broadly protective in experimental models of inflammation . Recombinant A box was antagonistic to B box and full‐length HMGB1 and is thought to compete with HMGB1 for receptor activation .…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%