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* Center for Vascular and Inflammatory Diseases and Departments of Surgery and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201;
Department of Pathology, Duke University Medical Center, Durham, NC 27710;
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556;
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697; and
¶ Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, IN 46617
C1q and members of the defense collagen family are pattern recognition molecules that bind to pathogens and apoptotic cells and trigger a rapid enhancement of phagocytic activity. Candidate phagocytic cell receptors responsible for the enhancement of phagocytosis by defense collagens have been proposed but not yet discerned. Engagement of phagocyte surface-associated calreticulin in complex with the large endocytic receptor, low-density lipoprotein receptor-related protein 1 (LRP/CD91), by defense collagens has been suggested as one mechanism governing enhanced ingestion of C1q-coated apoptotic cells. To investigate this possibility, macrophages were derived from transgenic mice genetically deficient in LRP resulting from tissue-specific loxP/Cre recombination. LRP-deficient macrophages were impaired in their ability to ingest beads coated with an LRP ligand when compared with LRP-expressing macrophages, confirming for the first time that LRP participates in phagocytosis. When LRP-deficient and -expressing macrophages were plated on C1q-coated slides, they demonstrated equivalently enhanced phagocytosis of sheep RBC suboptimally opsonized with IgG or complement, compared with cells plated on control protein. In addition, LRP-deficient and -expressing macrophages ingested equivalent numbers of apoptotic Jurkat cells in the presence and absence of serum. Both LRP-deficient and -expressing macrophages ingested fewer apoptotic cells when incubated in the presence of C1q-deficient serum compared with normal mouse serum, and the addition of purified C1q reconstituted uptake to control serum levels. These studies demonstrate a direct contribution of LRP to phagocytosis and indicate that LRP is not required for the C1q-triggered enhancement of phagocytosis, suggesting that other, still undefined, receptor(s) exist to mediate this important innate immune function.
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.
1 This work was supported by the Duke University Medical Scientist Training Program, Grant T32 GM007171 from the National Institute of General Medical Sciences (to A.P.L.), T32 HL007698 (to A.P.L.), and National Institutes of Health Grants HL-24066 (to S.V.P.), AI-41090 (to A.J.T.), HL054710 (to D.K.S.), HL050784 (to D.K.S.) and AHA 0630068N (to S.S.B.).
2 Address correspondence and reprint requests to Dr. Suzanne S. Bohlson, Indiana University School of Medicine, 1234 Notre Dame Avenue, South Bend, IN 46617.
3 Abbreviations used in this paper: LRP, low-density lipoprotein receptor-related protein 1; BMDM, bone marrow-derived macrophage; CRT, calreticulin; EAIgG, sheep erythrocytes opsonized with IgG; EAIgMC4b, sheep erythrocytes opsonized with complement component C4b; HBD, heparin binding domain; HSA, human serum albumin; macLRP, LRP-deficient macrophages; NMS, normal mouse serum; RAP, receptor-associated protein.
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