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Aiyappa Palecanda^*, Joseph Paulauskis^*, Eiman Al-Mutairi^*, Amy Imrich^*, Guozhong Qin^*, Hiroshi Suzuki, Tatsuhiko Kodama, Karl Tryggvason^||, Henry Koziel^¶, and Lester Kobzik

From the ^* Physiology Program, Harvard School of Public Health, Boston, Massachusetts 02115; the Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115; the Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153, Japan; the ^|| Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; and the ^¶ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

Alveolar macrophages (AMs) avidly bind and ingest unopsonized environmental particles and bacteria through scavenger-type receptors (SRs). AMs from mice with a genetic deletion of the major macrophage SR (types AI and AII; SR^–/–) showed no decrease in particle binding compared with SR^+/+ mice, suggesting that other SRs are involved. To identify these receptors, we generated a monoclonal antibody (mAb), PAL-1, that inhibits hamster AM binding of unopsonized particles (TiO₂, Fe₂O₃, and latex beads; 66 ± 5, 77 ± 2, and 85 ± 2% inhibition, respectively, measured by flow cytometry). This antibody identifies a protein of 70 kD on the AM surface (immunoprecipitation) that is expressed by AMs and other macrophages in situ. A cDNA clone encoding the mAb PAL-1–reactive protein isolated by means of COS cell expression was found to be 84 and 77% homologous to mouse and human scavenger receptor MARCO mRNA, respectively. Transfection of COS cells with MARCO cDNA conferred mAb-inhibitable TiO₂ binding. Hamster MARCO also mediates AM binding of unopsonized bacteria (67 ± 5 and 47 ± 4% inhibition of Escherichia coli and Staphylococcus aureus binding by mAb PAL-1). A polyclonal antibody to human MARCO identified the expected 70-kD band on Western blots of lysates of normal bronchoalveolar lavage (BAL) cells (>90% AMs) and showed strong immunolabeling of human AMs in BAL cytocentrifuge preparations and within lung tissue specimens. In normal mouse AMs, the anti-MARCO mAb ED31 also showed immunoreactivity and inhibited binding of unopsonized particles (e.g., TiO₂ 40%) and bacteria. The novel function of binding unopsonized environmental dusts and pathogens suggests an important role for MARCO in the lungs' response to inhaled particles.

Key Words: MARCO • alveolar • macrophage • unopsonized • environmental particle

This study complies with National Institutes of Health guidelines and was approved by the Institutional Review Committees on Animals of the Harvard School of Public Health.

Abbreviations used: AM, alveolar macrophage; BAL, bronchoalveolar lavage; BSS, balanced salt solution; CS, chondroitin sulfate; PI, polyinosinic acid; RAS, right angle scatter; SR, scavenger receptor; SRCR, scavenger receptor cysteine-rich domain.

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