Murine low-density lipoprotein receptor-related protein 1 (LRP) is required for phagocytosis of targets bearing LRP ligands but is not required for C1q-triggered enhancement of phagocytosis.
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.
Center for Vascular and Inflammatory Diseases and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Anna P
AP
Lillis
Mallary C
MC
Greenlee
Irina
I
Mikhailenko
Salvatore V
SV
Pizzo
Andrea J
AJ
Tenner
Dudley K
DK
Strickland
Suzanne S
SS
Bohlson
D000818:Animals; D017209:Apoptosis; D001853:Bone Marrow / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D015922:Complement C1q / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis; D012995:Solubility
D007136:Immunoglobulins; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D015922:Complement C1q