Innate immune collectin surfactant protein D enhances the clearance of DNA by macrophages and minimizes anti-DNA antibody generation.
Dying microbes and necrotic cells release highly viscous DNA that induces inflammation and septic shock, and apoptotic cells display DNA, a potential autoantigen, on their surfaces. However, innate immune proteins that mediate the clearance of free DNA and surface DNA-containing cells are not clearly established. Pulmonary surfactant proteins (SP-) A and D are innate immune pattern recognition collectins that contain fibrillar collagen-like regions and globular carbohydrate recognition domains (CRDs). We have recently shown that collectins SP-A, SP-D, and mannose binding lectin recognize DNA and RNA via their collagen-like regions and CRDs. Here we show that SP-D enhances the uptake of Cy3-labeled fragments of DNA and DNA-coated beads by U937 human monocytic cells, in vitro. Analysis of DNA uptake by freshly isolated mouse alveolar macrophages shows that SP-D, but not SP-A, deficiency results in reduced clearance of DNA, ex vivo. Analysis of bronchoalveolar lavage fluid shows that SP-D- but not SP-A-deficient mice are defective in clearing free DNA from the lung. Additionally, both SP-A- and SP-D-deficient mice accumulate anti-DNA Abs in sera in an age-dependent manner. Thus, we conclude that collectins such as SP-A and SP-D reduce the generation of anti-DNA autoantibody, which may be explained in part by the defective clearance of DNA from the lungs in the absence of these proteins. Our findings establish two new roles for these innate immune proteins and that SP-D enhances efficient pinocytosis and phagocytosis of DNA by macrophages and minimizes anti-DNA Ab generation.
Palaniyar
Nades
N
Medical Research Council Immunochemistry Unit, Department of Biochemistry, University of Oxford, UK. nades.palaniyar@sickkids.ca
Clark
Howard
H
Nadesalingam
Jeya
J
Shih
Michael J
MJ
Hawgood
Samuel
S
Reid
Kenneth B M
KB
D000276:Adjuvants, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis* / Q000097:blood; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D004247:DNA / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010873:Pinocytosis / Q000235:genetics / Q000276:immunology; D010957:Plasmids / Q000378:metabolism; D037662:Pulmonary Surfactant-Associated Protein A / Q000172:deficiency / Q000235:genetics; D037663:Pulmonary Surfactant-Associated Protein D / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020298:U937 Cells
D000276:Adjuvants, Immunologic; D000974:Antibodies, Antinuclear; D001324:Autoantigens; D037662:Pulmonary Surfactant-Associated Protein A; D037663:Pulmonary Surfactant-Associated Protein D; D004247:DNA