Sustained IL-4 exposure leads to a novel pathway for hemophagocytosis, inflammation, and tissue macrophage accumulation.
Erythrophagocytosis and inflammation from activated macrophages occur in distinct clinical scenarios. The presence of CD8(+) T cells and interferon-γ (IFN-γ) production is required to induce disease in mouse models of hemophagocytic lymphohistiocytosis. We investigated the roles of a different class of proinflammatory cytokines, interleukin-4 (IL-4) and IL-13, in the induction of inflammatory tissue macrophage accumulation and/or hemophagocytosis. We found that large amounts of IL-4, but not IL-13, delivered via an implanted mini-pump or IL-4/anti-IL-4 complexes, lead to substantial YM1(+) tissue macrophage accumulation, erythrophagocytosis within the liver, spleen, and bone marrow, decreased hemoglobin and platelet levels, and acute weight loss. This effect is not dependent on the presence of antibody or T cells, as treatment of Rag2(-/-) mice leads to similar disease, and IFN-γ neutralization during IL-4 treatment had no effect. IL-4 treatment results in suppression of IL-12, elevation of serum IFN-γ, IL-10, and the murine IL-8 homolog KC, but not IL-6, IL-1β, or tumor necrosis factor-α. Finally, mice transgenic for IL-4 production developed tissue macrophage accumulation, disruption of splenic architecture, bone marrow hypocellularity, and extramedullary hematopoiesis. These data describe a novel pathophysiologic pathway for erythrophagocytosis in the context of tissue macrophage accumulation and inflammation involving elevations in IL-4 and alternative macrophage activation.
Milner
Joshua D
JD
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD 20892, USA. jdmilner@niaid.nih.gov
Orekov
Tatyana
T
Ward
Jerrold M
JM
Cheng
Lily
L
Torres-Velez
Fernando
F
Junttila
Ilkka
I
Sun
Guangping
G
Buller
Mark
M
Morris
Suzanne C
SC
Finkelman
Fred D
FD
Paul
William E
WE
D000818:Animals; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D004912:Erythrocytes / Q000166:cytology; D005786:Gene Expression Regulation; D006965:Hyperplasia / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D018793:Interleukin-13 / Q000276:immunology*; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D007728:Kupffer Cells / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000166:cytology* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010587:Phagocytosis
D018793:Interleukin-13; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma