Macrophage response to apoptotic cells varies with the apoptotic trigger and is not altered by a deficiency in LRP expression.
Rapid engulfment of apoptotic cells in the absence of inflammation is required for maintenance of normal tissue homeostasis. The low-density lipoprotein receptor-related protein-1 (LRP/CD91) is a receptor mediating interactions between macrophages and apoptotic cells, but recent reports have challenged the requirement of this surface protein in this process. To explore the role of LRP in the recognition of apoptotic cells, target cells were generated with two distinct inducers of apoptotic cell death, etoposide and actinomycin-D. Jurkat T cells rendered apoptotic with etoposide exposed phosphatidylserine (PtdSer) and triggered engulfment by murine bone marrow-derived macrophages (BMDM), however they failed to suppress lipopolysaccharide-driven inflammatory cytokine secretion or, correspondingly, NF kappaB-dependent or TNFalpha promoter-driven transcriptional activity in transfected RAW264.7 macrophages. In contrast, induction of apoptosis in either Jurkat cells or HeLa epithelial cells with actinomycin-D resulted in diminution of proinflammatory signaling from RAW264.7 cells and BMDM. Treatment of actinomycin-treated Jurkat cells with Q-VD-OPh, an irreversible inhibitor of caspase activity, blocked apoptosis, as assessed by the inhibition of PtdSer exposure; however, the cells maintained anti-inflammatory activity. Anti-inflammatory signaling mediated by actinomycin-treated cells was not affected by a macrophage-specific deletion in LRP. Moreover, the presence of LRP on macrophages did not alter the efficiency of engulfment of apoptotic cells in vitro or in vivo. These data demonstrate that the method of induction of apoptosis of target cells influences subsequent macrophage responsiveness, and that LRP is not required for engulfment of apoptotic cells regardless of the method of induction.
Kozmar
Ana
A
Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, Indiana 46617, USA.
Greenlee-Wacker
Mallary C
MC
Bohlson
Suzanne S
SS
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D061945:Caspase Inhibitors; D003609:Dactinomycin / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011804:Quinolines / Q000494:pharmacology; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D000893:Anti-Inflammatory Agents; D000972:Antineoplastic Agents, Phytogenic; D061945:Caspase Inhibitors; D026502:LDL-Receptor Related Proteins; D008070:Lipopolysaccharides; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; C468548:quinoline-val-asp(OMe)-CH2-OPH; D003609:Dactinomycin; D005047:Etoposide