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.
Lillis
Anna P
AP
Center for Vascular and Inflammatory Diseases and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Greenlee
Mallary C
MC
Mikhailenko
Irina
I
Pizzo
Salvatore V
SV
Tenner
Andrea J
AJ
Strickland
Dudley K
DK
Bohlson
Suzanne S
SS
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