Molecular mechanisms of innate immune host defense mediated by lung-surfactant proteins A and D

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Pulmonary surfactant proteins A and D (SP-A and SP-D) belong to the collectin subgroup of C-type lectin superfamily, along with mannose binding proteins. The collecting bind to bacterial components in addition to certain phospholipids and glyco-sphingolipids and interact with macrophages. The proteins have been known to play critical roles in innate immunity of the lung. CD14 and Toll-like receptors (TLR) function as pathogen receptors (pattern recognition receptors) and are essential for recognition and signal transduction of various pathogen. The purpose of this study was to investigate molecular mechanisms of innate immunity mediated by surfactant proteins and pattern recognition receptors.(1)Lung collecting SP-A arid SP-D, bind CD14 by different mechanisms. They alter LPS-CD14 interactions. MBP also binds CD14, suggesting that binding to CD14 is a unique property of collectin group.(2) Peptidoglycan (PGN) derived from Staphylococcus aureus is not a ligand for SP-A. SP-A significantly attenuates PGN-elicited TNF-alpha in U937 cells and rat alveolar macrophages. SP-A attenuates PGN-induced NF-kappa activation in HEK293 cells transfected with TLR2 CDNA. In addition, SP-A binds the soluble form of the extracellular TLR2 domain (sTLR2) which was produced in culovirus-irisect cell system, and alters the binding of sTLR2 to PGN. These results demonstrate that SP-A inhibits PGN-induced TNF-alpha secretion by direct interaction with TLR2.(3) The extracellular TLR2 domain has been onstrated to bind directlt to PGN, indicating the direct interaction of TLR2 with PGN activate NF-kappa B.(4) Analaysis with CD14/TLR2 chimera in which CD14 was substituted for the extracellular TLR2 domain has demonstrated that CD14 cannot functionally replace with the extracellular TLR2 domain. The studies with- several deletion mutants of TLR2 also demonastrate that the extracellular TLR2 region of ser40-Ile64 but not the region of Cys30-Ser39 is critical for PGN signaling mediated by TLR2.