The Role of Collectins and Galectins in Lung Innate Immune Defense

Abstract

Different families of endogenous lectins use complementary defense strategies against pathogens. They may recognize non-self glycans typically found on pathogens and/or host glycans. The collectin and galectin families are prominent examples of these two lectin categories. Collectins are C-type lectins that contain a carbohydrate recognition domain and a collagen-like domain. Members of this group include surfactant protein A (SP-A) and D (SP-D), secreted by the alveolar epithelium to the alveolar fluid. Lung collectins bind to several microorganisms, which results in pathogen aggregation and/or killing, and enhances phagocytosis of pathogens by alveolar macrophages. Moreover, SP-A and SP-D influence macrophage responses, contributing to resolution of inflammation, and SP-A is essential for tissue-repair functions of macrophages. Galectins also function by interacting directly with pathogens or by modulating the immune system in response to the infection. Direct binding may result in enhanced or impaired infection of target cells, or can have microbicidal effects. Immunomodulatory effects of galectins include recruitment of immune cells to the site of infection, promotion of neutrophil function, and stimulation of the bactericidal activity of infected macrophages. Moreover, intracellular galectins can serve as danger receptors, promoting autophagy of the invading pathogen. This review will focus on the role of collectins and galectins in pathogen clearance and immune response activation in infectious diseases of the respiratory system.

Keywords: alternatively activated macrophages; autophagy; infection; inflammation; lung homeostasis; respiratory pathogens; surfactant proteins; tissue repair.

Figure 1

(A) Structural analysis of human collectins. Domain organization of human collectin polypeptide chains and the number of amino acids covering each domain are shown. Interruptions in the collagen domain of SP-A and MBL are indicated. Three-dimensional models of collectin oligomers are also shown. Trimers of collectins are each built up by the association of three polypeptide chains, the collagen regions of which intertwine to form a collagen triple helix. Whereas all other collectins are soluble, CL-P1 is a transmembrane protein orientated with its N-terminal toward the cytosol. CL-P1 may be regarded as both a collectin and a scavenger receptor. The scissors symbol means the shedding of a soluble form of CL-P1 by a hitherto unknown mechanism, which results in the presence of soluble CL-P1 in the circulation. The molecules are not drawn to scale. SP, signal peptide; NHt, N-terminal domain; COL, collagen-like domain; α-C, α-helical coiled-coil domain; CRD, carbohydrate recognition domain; TM, transmembrane domain. (B) Role of lung collectins on sequential type 1 and type 2 immune responses following respiratory infection. Respiratory pathogens are detected by AECs and aMΦs, initiating an innate immune response to clear localized infections. The type 1 response is essential in controlling infection but also induces tissue damage. Stimulated tissue-resident lymphoid cells and AECs release appropriate second-order cytokines that initiate a two-tiered response. The type 2 response, amplified by lung collectins (14), modulates aMΦs toward an anti-inflammatory resolving phenotype involved in lung repair. The role of lung collectins in these homeostatic changes is shown by small green or red arrows, which mean SP-A/D-mediated activation or inhibition, respectively.

Figure 2

Galectin activities in respiratory infections. (A) Binding to pathogens. Gal-3, the only chimera-type galectin described to date, binds bacterial mycolic acids, lipopolysaccharides, and cells, and also C. neoformans cells with antifungal effects. Gal-8 binds NTHi, decreasing bacterial viability (left side). Gal-1 binding to influenza virus blocks infection, while binding to NiV and S. pneumoniae bridges pathogen and host glycans (right side). (B) Effects on immune cells. Oligomerized Gal-3 can bridge neutrophils to endothelial cells. Depending on the pathogen, Gal-3 drives a Th2-polarized response, decreases macrophage and Th1 cell responses, or activates macrophages and/or neutrophils, similarly to Gal-9. In histoplasmosis, Gal-3 decreases cytokine production by dendritic cells, while Gal-1 modulates PGE2 and NO levels (left). Via TIM-3 binding, Gal-9 may promote bacterial killing by neutrophils or macrophages, decrease humoral and CD8+ cell responses or Th17 cells and IL-17 levels, and increase Treg cells (right). (C) Intracellular functions. Gal-3, -8, and -9 bind to host glycans in the luminal side of lysed phagosomes or permeable replicative vacuoles, and contribute to the autophagic response by recruiting NDP52, parkin, GBPs, or TRIM-16. Gal-8 also recruits parkin to group A Streptococcus.