Knockdown of a regulatory barcode shifts macrophage polarization destination from M1 to M2 and increases pathogen burden upon S. aureus infection.

A three-factor regulatory set (CEBPB, NFE2L2, BCL3) is sufficient to shift THP1-derived macrophages from an M1 to an M2 polarization destination.

• Why it matters: The study addresses a gap in knowing which transcriptional regulators specify the exact macrophage polarization state elicited by a given immune stimulus.
• What they did: It analyzed macrophage transcriptomes under 28 distinct stimuli to reconstruct contextualized human gene regulatory networks, yielding 13 clusters spanning M1 to M2, then tested a 3-RF-set by siRNA knockdown in THP1-derived M0 cells.
• The result: Knocking down the 3-RF-set reduced the M1 shift and increased M2 marker expression, and it made macrophages hyper-susceptible to Staphylococcus aureus infection.

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