SP-D and regulation of the pulmonary innate immune system in allergic airway changes

Abstract

The airway mucosal surfaces are constantly exposed to inhaled particles that can be potentially toxic, infectious or allergenic and should elicit inflammatory changes. The proximal and distal air spaces, however, are normally infection and inflammation free due to a specialized interplay between cellular and molecular components of the pulmonary innate immune system. Surfactant protein D (SP-D) is an epithelial-cell-derived immune modulator that belongs to the small family of structurally related Ca(2+)-dependent C-type collagen-like lectins. While collectins can be detected in mucosal surfaces of various organs, SP-A and SP-D (the 'lung collectins') are constitutively expressed in the lung at high concentrations. Both proteins are considered important players of the pulmonary immune responses. Under normal conditions however, SP-A-/- mice display no pathological features in the lung. SP-D-/- mice, on the other hand, show chronic inflammatory alterations indicating a special importance of this molecule in regulating immune homeostasis and the function of the innate immune cells. Recent studies in our laboratory and others implied significant associations between changes in SP-D levels and the presence of airway inflammation both in animal models and patients raising a potential usefulness of this molecule as a disease biomarker. Research on wild-type and mutant recombinant molecules in vivo and in vitro showed that SP-D binds carbohydrates, lipids and nucleic acids with a broad spectrum specificity and initiates phagocytosis of inhaled pathogens as well as apoptotic cells. Investigations on gene-deficient and conditional over expressor mice in addition, provided evidence that SP-D directly modulates macrophage and dendritic cell function as well as T cell-dependent inflammatory events. Thus, SP-D has a unique, dual functional capacity to induce pathogen elimination on the one hand and control of pro-inflammatory mechanisms on the other, suggesting a potential suitability for therapeutic prevention and treatment of chronic airway inflammation without compromising the host defence function of the airways. This paper will review recent findings on the mechanisms of immune-protective function of SP-D in the lung.

Fig. 1.

The ‘Head or Tail Hypothesis’ (adapted from Gardai et al. [109]): SP-D is capable of differential binding through either the CRD or the collagen domain to cell membrane receptors and eliciting respective anti- or pro-inflammatory, signalling pathways. (A) SP-D is assembled as a lectin head containing the carbohydrate recognition domain (CRD), a neck region and a collagenous tail. SP-D (a 43 kDa monomer) under normal baseline conditions forms a higher order quaternary structure (usually a dodecamer) assembled from four homotrimers with the N-terminal collagen tail of the molecule hidden in the centre of the oligomeric structures bound together by cysteine residues. The C-terminal CRD binding to signal inhibitory regulatory protein (SIRP-α) inhibits cytokine production [109]. SIRP-α is expressed on dendritic cells and macrophages. It contains two ITIM as well as two immunoreceptor tyrosine-based switch-like motifs, which recruit Src homology region 2 domain-containing phosphatase (SHP)-1 and -2, thus inhibiting intracellular signalling [138]. (B) When the collagen domain of SP-D is exposed in lower oligomers (trimers), it can initiate binding to the collagen-receptor calreticulin/CD91. Ligation of this receptor complex induces pro-inflammatory cellular functions mediated by the activation of p38 and NF-κB signalling molecules. Oxidative changes under pro-inflammatory circumstances can alter the structure of the native SP-D [119, 120, 143] leading to an impaired inhibitory function of the CRD [143] or de-oligomerization of the SP-D molecule from dodecameric to trimeric forms exposing the otherwise hidden N-terminal collagen domain [119].

Fig. 2.

Hypothetic role of SP-D in dendritic cell migration. In Aspergillus fumigatus-induced allergic airway inflammation, the Ccl17-Ccr4 and Ccl19/21-Ccr7 ligand–receptor pairs were significantly up-regulated at the mRNA level in a time-dependent manner in mice [4, 165, 166]. (a) SP-D prevents the epithelial migration of myeloid dendritic cells by inhibiting autocrine Ccl17 release. Ccl17 (thymus and activation-regulated chemokine, TARC) is responsible for attracting Th2 lymphocytes and activated myeloid dendritic cells to the airway submucosal tissue through its receptor, Ccr4 which is expressed specifically on Th2 cells and activated dendritic cells. (b) SP-D promotes the uptake of inhaled pathogens and the migration towards the mediastinal lymph nodes. In addition to the initiation of naïve T cells, lymph-node-directed migration serves the purpose of confining the immune response to the lymphoid area leaving the airways pathogen and inflammation free. This process is driven by Ccl19 or Ccl21, both of which act on the chemokine receptor Ccr7.