Cholesterol-induced apoptotic macrophages elicit an inflammatory response in phagocytes, which is partially attenuated by the Mer receptor.
Macrophage apoptosis and the ability of phagocytes to clear these apoptotic cells are important processes in advanced atherosclerosis. Phagocytic clearance not only disposes of dead cells but usually elicits an anti-inflammatory response. To study this process in a model of advanced lesional macrophage death, macrophages rendered apoptotic by free cholesterol loading (FC-AMs) were incubated briefly with fresh macrophages ("phagocytes"). FC-AMs were promptly ingested by the phagocytes, which was dependent upon actin polymerization and the phagocyte Mer receptor. Surprisingly, this brief exposure to FC-AMs triggered a modest proinflammatory response in the phagocytes: tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta were induced, whereas the levels of transforming growth factor-beta and IL-10 were not increased. This response required cell contact between the FC-AMs and phagocytes but not FC-AM ingestion. TNF-alpha and IL-1beta induction required one or more proteins on the FC-AM surface and was dependent on signaling through extracellular signal-regulated kinase-1/2 mitogen-activated protein kinase and nuclear factor-kappaB in the phagocytes. TNF-alpha production was markedly greater when Mer-defective phagocytes were used, indicating that Mer attenuated the inflammatory response. Interestingly, a more typical anti-inflammatory response was elicited when phagocytes were exposed to macrophages rendered apoptotic by oxidized low density lipoprotein or UV radiation. Thus, the proinflammatory milieu of advanced atherosclerotic lesions may be promoted, or at least not dampened, by contact between FC-induced apoptotic macrophages and neighboring phagocytes prior to apoptotic cell ingestion.
Li
Yankun
Y
Department of Medicine, Columbia University, New York, New York 10032, USA.
Gerbod-Giannone
Marie-Christine
MC
Seitz
Heather
H
Cui
Dongying
D
Thorp
Edward
E
Tall
Alan R
AR
Matsushima
Glenn K
GK
Tabas
Ira
I
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000502:physiology*; D005260:Female; D007375:Interleukin-1 / Q000096:biosynthesis; D016753:Interleukin-10 / Q000037:antagonists & inhibitors; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000076202:c-Mer Tyrosine Kinase
D048868:Adaptor Proteins, Signal Transducing; D007375:Interleukin-1; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D002784:Cholesterol; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase