Respiratory disordersLung infections and innate host defense
Section editor:
Clay Braden Marsh – Department of Internal Medicine, Ohio State University, USA
Introduction
Human lungs move around 14,000 L of air every day. Thus significant amounts of organic and inorganic particulates and microbes inhaled from the environment and aspirated from the posterior pharynx can reach the 150 m2 of alveolar surface. The integrity of the thin alveolar membrane is essential to assure oxygen and CO2 gas exchange; therefore the recognition and handling of these particulates without causing excessive inflammation are extremely important. Specialized lung innate immune responses play a key role in this process. Recognition of particulates is broad and based on use of pattern recognition receptors (PRRs); however, the immune responses following recognition in the lung are unique enabling dampening of pro-inflammation and thereby limiting damage to the alveolar surface. Alveolar macrophages (AMs) and dendritic cells (DC) are the first cellular line of defense in the alveoli and their surfaces are rich in PRRs. Evidence is accumulating that soluble and cell-associated C-type (Ca2+-dependent) lectins play a key role in shaping the innate response in the lung. In addition to the established role for Toll-like receptors (TLRs) in this process, recent evidence indicates that NOD (nucleotide-binding oligomerization domain)-like proteins (NLR) also play an important role as intracellular sensors that regulate inflammatory responses. Here we will discuss these important cellular and soluble determinants of the lung innate immune response, provide examples of their roles in modifying the host response to specific infectious agents during disease pathogenesis and address potential therapeutic applications.
Section snippets
Surfactant proteins A and D
The alveolar space consists of flat lining cells or type I cells important in gas exchange and type II cells that produce and secrete a mixture of proteins and phospholipids that comprise surfactant. Surfactant proteins B and C have important biological properties that result in lowering surface tension and preventing the alveoli from collapsing. A deficiency of these proteins in premature infants leads to infant respiratory distress syndrome, for which administration of exogenous surfactant is
Alveolar macrophages
Because of its location at the alveolar air tissue interface, the alveolar macrophage (AM) is the first line of cellular defense against inhaled environmental particles and infectious microorganisms that enter the lungs. These cells express several immune receptors, including Fc-γ receptors and complement receptors (e.g. CR1, CR3 and CR4); and particularly high levels of pattern recognition receptors such as the MR, Dectin-1 (β-glucan receptor), scavenger receptors, Toll-like receptors and
The mannose receptor
The mannose receptor (MR) is a C-type lectin that is expressed on tissue macrophages, AMs and DCs but not monocytes [53, 54, 55]. The MR is a Type I transmembrane protein with a short cytoplasmic tail and an extracellular domain that shares homology with other C-type lectins. The extracellular domain is a PRR that binds with high affinity to mannose- and fucose-containing glycoconjugates frequently found on the surface of a variety of microbes referred to as pathogen-associated molecular
DC-SIGN
Dendritic cells are a diverse group of myeloid and lymphoid-origin cells that play a key role in the adaptive immune response. One way these cells can regulate this immune response is through the expression of major pattern recognition receptors [67]. The DC-specific ICAM-grabbing non-integrin (DC-SIGN, CD209) is a C-type lectin that binds to HIV gp120 [68, 69]. Like the MR, DC-SIGN has an extracellular CRD. Its cytoplasmatic domain is important for antigen internalization and signal
Dectin-1
This C-type lectin is expressed on macrophages, DCs and neutrophils and is primarily a PRR for fungal β-glucan [74, 78]. It contains an extracellular CRD and an intracellular immunoreceptor tyrosine-based activation motif (ITAM) required for interactions with TLR2 [74] and the cytoskeletal changes that occur after Dectin-1 mediated phagocytosis [79]. A unique feature of Dectin-1 is that it mediates the production of TNF-α in response to C. albicans and Streptomyces cerevisiae [80]. The
Toll-like receptors
Toll-like receptors are membrane-associated type I receptors that largely function to recognize PAMPs [83]. There are 11 mammalian TLRs which vary in function largely with respect to the ligands that they recognize [84]. The externalized amino terminus contains variable arrangements of leucine-rich repeats (LRRs) which serve to recognize the PAMPs. The cytosolic carboxy terminus of TLRs is highly homologous to the IL-1 receptor and contains a Toll/IL-1R (TIR) domain that forms the nidus for the
NOD proteins
Although surface PRRs such as TLRs are widely recognized regulators of immune responses, 23 cytosolic NOD-like receptors (NLRs) implicated in the innate recognition of intracellular pathogens have been recently described [87, 88, 89, 90, 91, 92]. They are composed of a C-terminal series of leucine-rich repeats similar to the extracellular domain of TLRs, a central nucleotide-oligomerization domain and an amino-terminal protein–protein interaction domain, such as caspase activation and
Mannose binding lectin (MBL)
The mannose binding lectin (MBL) is a soluble collectin present in serum [113]. Like other collectins, it serves as a PRR for microorganisms. There is increasing evidence that polymorphisms in the MBL are associated with different types of infections such as HIV, cryptosporidiosis, meningococcal disease and tuberculosis [114, 115, 116, 117].
M. tuberculosis
M. tuberculosis is an intracellular pathogen of mononuclear phagocytes and highly adapted to the human host. This bacterium enters macrophages by the phagocytic process using a defined subset of receptors, and subsequently multiplies within a unique phagosomal compartment. SP-A and SP-D regulate the early interaction between M. tuberculosis and macrophages. SP-A increases the phagocytosis of M. tuberculosis through a direct interaction of the protein with macrophages [118], which up-regulates
Future directions and therapeutic options
For more than 25 years surfactant therapy has been successfully used in neonates with respiratory distress syndrome with the purpose of facilitating alveolar gas interchange. Surfactant therapy has also been used in adults with acute respiratory distress syndrome (ARDS) without benefit [138]. However, surfactant replacement therapy has been based on the biomechanical properties of surfactant rather than its biological properties, and neither SP-A nor SP-D are components of artificial
Acknowledgment
Part of the research was supported by NIH Grants A1052458 and A1059639.
References (144)
Surfactant protein A limits Pneumocystis murina infection in immunosuppressed C3H/HeN mice and modulates host response during infection
Microbes Infect.
(2005)- et al.
The lung collectins, SP-A and SP-D, modulate pulmonary innate immunity
Mol. Immunol.
(2005) Lipoglycans are putative ligands for the human pulmonary surfactant protein A attachment to mycobacteria. Critical role of the lipids for lectin-carbohydrate recognition
J. Biol. Chem.
(2000)Human pulmonary surfactant protein (SP-A), a protein structurally homologous to C1q, can enhance FcR- and CR1-mediated phagocytosis
J. Biol. Chem.
(1989)Pulmonary surfactant protein A augments the phagocytosis of Streptococcus pneumoniae by alveolar macrophages through a casein kinase 2-dependent increase of cell surface localization of scavenger receptor A
J. Biol. Chem.
(2004)By binding SIRPalpha or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation
Cell
(2003)Surfactant protein A inhibits peptidoglycan-induced tumor necrosis factor-alpha secretion in U937 cells and alveolar macrophages by direct interaction with toll-like receptor 2
J. Biol. Chem.
(2002)Association between the surfactant protein A (SP-A) gene locus and respiratory-distress syndrome in the Finnish population
Am. J. Hum. Genet.
(2000)- et al.
Purification of the human alveolar macrophage mannose receptor
Biochem. Biophys. Res. Commun.
(1987) Alveolar macrophage in the driver's seat
Immunity
(2006)
Induction of a homeostatic circuit in lung tissue by microbial compounds
Immunity
The mannose receptor is a pattern recognition receptor involved in host defense
Curr. Opin. Immunol.
Receptor-mediated pinocytosis of mannose glycoconjugates by macrophages: characterization and evidence for receptor recycling
Cell
The mannose receptor delivers lipoglycan antigens to endosomes for presentation to T cells by CD1b molecules
Immunity
Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses
Cell
DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells
Cell
DC-SIGN and LFA-1: a battle for ligand
Trends Immunol.
Ligand recognition by antigen-presenting cell C-type lectin receptors
Curr. Opin. Immunol.
Dectin-1 uses novel mechanisms for yeast phagocytosis in macrophages
Blood
The beta-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria
Blood
Pathogen recognition and innate immunity
Cell
Human CARD4 protein is a novel CED-4/Apaf-1 cell death family member that activates NF-kappaB
J. Biol. Chem.
Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB
J. Biol. Chem.
Human Nod1 confers responsiveness to bacterial lipopolysaccharides
J. Biol. Chem.
Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kappa B activation
J. Biol. Chem.
Peptidoglycan signaling in innate immunity and inflammatory disease
J. Biol. Chem.
Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB
J. Biol. Chem.
Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection
J. Biol. Chem.
Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease
J. Biol. Chem.
Surfactant protein A and surfactant protein D in health and disease
Am. J. Physiol.
The human mannose-binding protein functions as an opsonin
J. Exp. Med.
The roles of surfactant proteins A and D in innate immunity
Immunol. Rev.
Distinct effects of surfactant protein A or D deficiency during bacterial infection on the lung
J. Immunol.
Surfactant protein-A-deficient mice are susceptible to Pseudomonas aeruginosa infection
Am. J. Respir. Cell Mol. Biol.
Immunosuppressed surfactant protein A-deficient mice have increased susceptibility to Pneumocystis carinii infection
J. Infect. Dis.
Binding of surfactant protein A to the lipid A moiety of bacterial lipopolysaccharides
Biochem. J.
Interactions of surfactant protein D with bacterial lipopolysaccharides. Surfactant protein D is an Escherichia coli-binding protein in bronchoalveolar lavage
J. Clin. Invest.
Surfactant protein D binds to Mycobacterium tuberculosis bacilli and lipoarabinomannan via carbohydrate-lectin interactions resulting in reduced phagocytosis of the bacteria by macrophages
J. Immunol.
Pulmonary surfactant protein A enhances the host-defense mechanism of rat alveolar macrophages
Am. J. Respir. Cell Mol. Biol.
SP-A enhances phagocytosis of Klebsiella by interaction with capsular polysaccharides and alveolar macrophages
Am. J. Physiol.
Binding of surfactant protein A to C1q receptors mediates phagocytosis of Staphylococcus aureus by monocytes
Am. J. Physiol.
Pulmonary surfactant proteins A and D enhance neutrophil uptake of bacteria
Am. J. Physiol.
Surfactant protein A stimulates phagocytosis of specific pulmonary pathogens by alveolar macrophages
Am. J. Physiol.
Pulmonary surfactant protein A up-regulates activity of the mannose receptor, a pattern recognition receptor expressed on human macrophages
J. Immunol.
Pulmonary collectins enhance phagocytosis of Mycobacterium avium through increased activity of mannose receptor
J. Immunol.
Pulmonary surfactant protein A activates a phosphatidylinositol 3-kinase/calcium signal transduction pathway in human macrophages: participation in the up-regulation of mannose receptor activity
J. Immunol.
Surfactant-associated protein A inhibits LPS-induced cytokine and nitric oxide production in vivo
Am. J. Physiol. Lung Cell Mol. Physiol.
Pulmonary surfactant protein a inhibits macrophage reactive oxygen intermediate production in response to stimuli by reducing NADPH oxidase activity
J. Immunol.
Surfactant proteins as genetic determinants of multifactorial pulmonary diseases
Ann. Med.
Family-based transmission disequilibrium test (TDT) and case-control association studies reveal surfactant protein A (SP-A) susceptibility alleles for respiratory distress syndrome (RDS) and possible race differences
Clin. Genet.
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