Apoptotic Cells and Innate Immune Stimuli Combine to Regulate Macrophage Cytokine Secretion

Abstract

Macrophage interactions with apoptotic cells can suppress inflammatory responses, but cell death by apoptosis may also trigger inflammation. We now report that murine macrophages exposed to the combination of apoptotic cells and archetypal ligands for Toll-like receptors (TLRs) 2, 4, and 9 mount cytokine responses that differ importantly from those elicited by either class of stimulus alone. TLR ligands induced early and sustained secretion of TNF-α, macrophage-inflammatory protein (MIP) 1α and MIP-2 with later secretion of IL-10, IL-12, and TGF-β1; apoptotic cells alone stimulated late TGF-β1 secretion only. The combination of apoptotic cells and TLR ligands enhanced early secretion of TNF-α, MIP-1α, and MIP-2 and increased late TGF-β1 secretion, while suppressing late TNF-α, IL-10, and Il-12 by mechanisms which could nevertheless be overridden by IFN-γ. We propose that this combinatorial macrophage cytokine response to apoptotic cells and TLR ligands may contribute to recruitment and activation of innate immune defense when cell death occurs at infected inflamed sites while promoting later resolution with diminished engagement of adaptive immunity.