Single-cell secretion analysis reveals a dual role for IL-10 in restraining and resolving the TLR4-induced inflammatory response [article]

Amanda F Alexander, Hannah Forbes, Kathryn Miller-Jensen
2020 bioRxiv   pre-print
Following TLR4 stimulation of macrophages, negative feedback mediated by the anti-inflammatory cytokine IL-10 limits the inflammatory response. However, extensive cell-to-cell variability in TLR4-stimulated cytokine secretion raises questions about how negative feedback is robustly implemented. To explore this, we characterized the TLR4-stimulated secretion program in primary murine macrophages using a single-cell microwell assay that enabled evaluation of functional autocrine IL-10 signaling.
more » ... igh-dimensional analysis of single-cell data revealed three distinct tiers of TLR4-induced proinflammatory activation based on levels of cytokine secretion. Surprisingly, while IL-10 inhibits TLR4-induced activation in the highest tier, it also contributes to the TLR4-induced activation threshold by regulating which cells transition from non-secreting to secreting states. This role for IL-10 in restraining TLR4 inflammatory activation is largely mediated by intermediate IFN-β signaling, while TNF-α likely mediates response resolution by IL-10. Thus, cell-to-cell variability in cytokine regulatory motifs provides a means to tailor the TLR4-induced inflammatory response.
doi:10.1101/2020.10.22.351254 fatcat:tmvh3hu7r5c7xpxid47pb376e4