Cytokine dysregulation induced by apoptotic cells is a shared characteristic of macrophages from nonobese diabetic and systemic lupus erythematosus-prone mice.
Macrophages from nonobese diabetic (NOD) mice, which spontaneously develop type I diabetes, share a defect in elicited cytokine production with macrophages from multiple diverse strains of systemic lupus erythematosus (SLE)-prone mice. We have previously shown that, in SLE-prone mice, this defect is triggered by exposure to apoptotic cells. We report in this work that macrophages from prediseased NOD mice also respond abnormally to apoptotic cells, mimicking closely the apoptotic cell-dependent abnormality that we have observed in multiple SLE-prone strains. This defect is characterized by the underexpression of IL-1 beta and multiple other cytokines. In the presence of apoptotic cells or FBS, elicited expression of IL-1 beta by NOD macrophages is markedly reduced compared with that by macrophages from control mice, including three strains of mice that develop type II (nonautoimmune) diabetes. Given the increasing role of apoptotic cells in tolerance and autoimmunity, a macrophage defect triggered by apoptotic cells has broad potential to upset the balance between tolerance and immunity. The concordance of this defect among so many diverse autoimmune-prone strains suggests that the genetic basis for this abnormality may constitute a permissive background for autoimmunity.
Fan
Hanli
H
Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Longacre
Angelika
A
Meng
Fanyong
F
Patel
Vimal
V
Hsiao
Kevin
K
Koh
Jason S
JS
Levine
Jerrold S
JS
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D005312:Fetal Blood / Q000502:physiology; D020022:Genetic Predisposition to Disease; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008055:Lipids / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic
D016895:Culture Media, Serum-Free; D016207:Cytokines; D007375:Interleukin-1; D008055:Lipids