Abstract
AbstractErythrophagocytosis 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.
Highlights
Erythrophagocytosis and accumulation and infiltration of macrophages in tissue occur in a limited set of conditions
We found that exposure to high concentrations of IL-4 via implanted mini-osmotic pumps or IL-4/anti–IL-4 immune complexes leads to severe histiocytosis and erythrophagocytosis within the liver and spleen, bone marrow erythrophagocytosis, and acute weight loss
Sustained exposure to high levels of IL-4 can induce a striking phenotype of erythrophagocytosis and tissue infiltration and/or accumulation of alternatively activated macrophages
Summary
Erythrophagocytosis and accumulation and infiltration of macrophages in tissue occur in a limited set of conditions. Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndromes are examples of disorders of abnormal, severe immune activation both characterized by fever, splenomegaly, histiocytic invasion of the liver, spleen, variably bone marrow, and other organs with accompanying engulfment of erythrocytes, and often a cytokine “storm” composed of numerous inflammatory cytokines.[1] These conditions are usually fatal if not treated with aggressive chemotherapy and, bone marrow transplantation. Acquired or secondary HLH can be induced by viral infection and may occur in visceral Leishmaniasis, autoimmune disease, and malignancy.[2] The precise pathogenesis of HLH is not well understood, it is thought that overproduction of macrophage-activating cytokines by lymphocytes is critical
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