Diverse functions of pulmonary collectins in host defense of the lung

Abstract

Pulmonary surfactant is a mixture of lipids and proteins that covers alveolar surfaces and keeps alveoli from collapsing. Four specific proteins have been identified in surfactant. Among them, two C-type lectins, surfactant proteins A and D (SP-A and SP-D), are known to be implicated in host defense and regulation of inflammatory responses of the lung. These host defense lectins are structurally characterized by N-terminal collagen-like domains and lectin domains and are called pulmonary collectins. They prevent dissemination of infectious microbes by their biological activities including agglutination and growth inhibition. They also promote clearance of microbes by enhancing phagocytosis in macrophages. In addition, they interact with the other pattern-recognition molecules, including Toll-like receptors (TLRs) and TLR-associated molecules, CD14 and MD-2, and regulate inflammatory responses. Furthermore, recent studies have demonstrated that these collectins modulate functions of neutrophil-derived innate immune molecules by interacting with them. These findings indicate that pulmonary collectins play critical roles in host defense of the lung.

Figure 1

Structural organization of pulmonary collectins. SP-A forms a bouquet-like octadecamer assembled from six trimers, while SP-D forms a cruciform dodecamer assembled from four trimers. A subpopulation of SP-D forms a multimerized oligomer associated with their N-termini.

Figure 2

Roles of pulmonary collectins in host defense against L. pneumophila. During infection, L. pneumophila secretes various effector molecules via type IV secretion system to manipulate the host cell immune responses. This results in pore-forming on host cell membrane. The secreted effector molecules enable L. pneumophila to bypass phagosomes-lysosome fusion and survive in characteristic vacuoles consisted of ER-derived membrane. Pulmonary collectins protect macrophage membrane against pore-forming activity of L. pneumophila. The collectins also attenuate intracellular growth of L. pneumophila in part by facilitating phagosomes-lysosome fusion.

Figure 3

Pulmonary collectins modulate inflammation via TLRs. Association of SP-A with TLR2 or TLR4/MD-2 complex results in the downregulation of inflammatory responses by inhibiting the recognition of non-SP-A ligands including smooth LPS, peptidoglycan, and zymosan via TLRs. In contrast, SP-A dose not inhibit secretion of proinflammatory cytokines induced by rough LPS, which is an SP-A ligand. Interaction of SP-D with TLR4/MD-2 complex inhibits proinflammatory cytokine production induced by both smooth and rough LPS.