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J. Biol. Chem., Vol. 279, Issue 31, 32728-32736, July 30, 2004

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Nucleic Acid Is a Novel Ligand for Innate, Immune Pattern Recognition Collectins Surfactant Proteins A and D and Mannose-binding Lectin^*

Nades Palaniyar¶, Jeya Nadesalingam, Howard Clark||, Michael J. Shih, Alister W. Dodds, and Kenneth B. M. Reid

From the MRC Immunochemistry Unit, Department of Biochemistry, The University of Oxford, Oxford OX1 3QU, United Kingdom and the Lung Biology Research Program, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 1X8, Canada

Collectins are a family of innate immune proteins that contain fibrillar collagen-like regions and globular carbohydrate recognition domains (CRDs). The CRDs of these proteins recognize various microbial surface-specific carbohydrate patterns, particularly hexoses. We hypothesized that collectins, such as pulmonary surfactant proteins (SPs) SP-A and SP-D and serum protein mannose-binding lectin, could recognize nucleic acids, pentose-based anionic phosphate polymers. Here we show that collectins bind DNA from a variety of origins, including bacteria, mice, and synthetic oligonucleotides. Pentoses, such as arabinose, ribose, and deoxyribose, inhibit the interaction between SP-D and mannan, one of the well-studied hexose ligands for SP-D, and biologically relevant D-forms of the pentoses are better competitors than the L-forms. In addition, DNA and RNA polymer-related compounds, such as nucleotide diphosphates and triphosphates, also inhibit the carbohydrate binding ability of SP-D, or 60 kDa trimeric recombinant fragments of SP-D that are composed of the -helical coiled-coil neck region and three CRDs (SP-D(n/CRD)) or SP-D(n/CRD) with eight GXY repeats (SPD(GXY)₈(n/CRD)). Direct binding and competition studies suggest that collectins bind nucleic acid via their CRDs as well as by their collagen-like regions, and that SP-D binds DNA more effectively than do SP-A and mannose-binding lectin at physiological salt conditions. Furthermore, the SP-D(GXY)₈(n/CRD) fragments co-localize with DNA, and the protein competes the interaction between propidium iodide, a DNA-binding dye, and apoptotic cells. In conclusion, we show that collectins are a new class of proteins that bind free DNA and the DNA present on apoptotic cells by both their globular CRDs and collagen-like regions. Collectins may therefore play an important role in decreasing the inflammation caused by DNA in lungs and other tissues.

Received for publication, April 5, 2004 , and in revised form, April 27, 2004.

^* This work was partially supported by research grants from the Medical Research Council, EU Framework 5 QL Contract 00325 (to J. N. and K. B. M. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Recipient of the Beit Memorial fellowship for medical research.

^¶ Recipient of the Wellcome Trust and Canadian Institutes of Health Research postdoctoral fellowships. To whom correspondence should be addressed: MRC Immunochemistry Unit, Dept. of Biochemistry, The University of Oxford, South Parks Rd., Oxford OX1 3QU, UK. E-mail: Nades{at}bioch.ox.ac.uk.

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