Pulmonary Surfactant Protein D Inhibits Lipopolysaccharide (LPS)-induced Inflammatory Cell Responses by Altering LPS Binding to Its Receptors

Abstract

Pulmonary surfactant protein D (SP-D) 3 is a member of the collectin protein family that also includes surfactant protein A (SP-A) and mannose binding lectin (1, 2). The structure of the collectins is characterized by four domains consisting of: 1) an N terminus involved in interchain disulfide bonding, 2) a collagen-like domain, 3) a coiled-coil neck domain, and 4) a carbohydrate recognition domain (CRD) (3). SP-A and mannose binding lectin contain collagenous domains consisting of 23 and 19 repeating Gly-X-Y triplets, respectively, with an interruption at the middle of the collagenous sequence (4, 5). In contrast, SP-D possesses a longer collagenous tail composed of 59 Gly-X-Y repeats without an interruption (6). These differences cause distinct oligomeric organization, with SP-A and mannose binding lectin exhibiting bouquet-like structures consisting of either six or four trimeric subunits (7) and SP-D exhibiting cruciform structures composed of four trimeric subunits (8).Lipopolysaccharide (LPS) is a principal component of the outer membrane of Gram-negative bacteria that activates macrophages and induces a variety of inflammatory mediators, including TNF-␣, IL-1, IL-6, IL-8, and interferon (9). LPS composed of O-antigen, core oligosaccharide, and lipid A is named smooth LPS, and LPS lacking O-antigen and a part of the core oligosaccharides is named rough LPS (10). Toll-like receptor 4 (TLR4) plays a critical role in recognition and signaling by LPS (11, 12). MD-2 binds directly to LPS and is required for TLR4-mediated signaling induced by LPS (13,14). Structural examination of the TLR4-MD-2 complex revealed that MD-2 binds to the concave surface of the N-terminal and central domains of TLR4 (15). A study with recombinant soluble forms of the extracellular TLR4 domain (sTLR4) and MD-2 (sMD-2) from our laboratory indicates the importance of the N-terminal region of TLR4 in MD-2 binding (16).Engineered genetic defects in the pulmonary collectins of mice have revealed their important functions in protecting the lung from microbial infections and inflammation. SP-D-null mice infected with group B Streptococcus or Haemophilus influenza by intra-tracheal instillation show increased inflammation and inflammatory cell recruitment in the lung (17). Increased pulmonary inflammation in LPS (Escherichia coli O55:B5, smooth serotype)-instilled SP-D Ϫ/Ϫ mice and wildtype mice was decreased by intratracheal administration of SP-D and pulmonary surfactant (18). Intratracheal recombinant SP-D prevents endotoxin shock in the newborn preterm

Surfactant protein D suppresses lung cancer progression by downregulation of epidermal growth factor signaling

“…8,9 In addition, SP-D interacts with the other pattern-recognition molecules including Toll-like receptors (TLRs) and TLR-associated molecules CD14 and MD-2, and regulates inflammatory responses. [10][11][12] It has been suggested that SP-D expression levels are inversely correlated with lung cancer progression. The genetic abnormalities in SP-D were associated with lung cancer pathogenesis.…”

Surfactant Protein-D Inhibits Lung Inflammation Caused by Ventilation in Premature Newborn Lambs

“…Initially, these are trimeric subunits stabilized by disulfide bonds; subsequently higher-order multimers produce a wheel-like dodecameric structure stabilized by interchain sulfhydryl bonds (37,38). SP-D structure is critical to its function (39). Although the carbohydrate recognition domain mediates its interactions with pathogens, several in vivo studies in which mutant or full-length SP-D were expressed in Sftpd 2/2 mice lungs suggest that the full function of SP-D is dependent on a full-length, multimeric protein (40)(41)(42)(43)(44)(45)(46).…”

Implication of Antigenic Conversion of Helicobacter pylori Lipopolysaccharides That Involve Interaction with Surfactant Protein D

“…The second is a modulatory effect on signal transduction. SP-D interacts with the extracellular domains of TLR4, TLR2, MD2, and the complex of TLR4-MD2 via its CRD (25,28,34). SP-D can inhibit LPSinduced signal transduction via TLRs independent of the presence of TLR ligands (34).…”